bims-tucedo Biomed News
on Tumor cell dormancy
Issue of 2020‒05‒17
27 papers selected by
Isabel Puig Borreil
Vall d’Hebron Institute of Oncology

  1. Cancer Discov. 2020 May 13. pii: CD-19-1390. [Epub ahead of print]
    Wander SA, Cohen O, Gong X, Johnson GN, Buendia-Buendia JE, Lloyd MR, Kim D, Luo F, Mao P, Helvie K, Kowalski KJ, Nayar U, Waks AG, Parsons SH, Martinez R, Litchfield LM, Ye XS, Yu C, Jansen VM, Stille JR, Smith PS, Oakley GJ, Chu QS, Batist G, Hughes ME, Kremer JD, Garraway LA, Winer EP, Tolaney SM, Lin NU, Buchanan SG, Wagle N.
      Mechanisms driving resistance to CDK4/6 inhibitors in HR+ breast cancer have not been clearly defined. Whole exome sequencing of 59 tumors with CDK4/6i exposure revealed multiple candidate resistance mechanisms including RB1 loss, activating alterations in AKT1, RAS, AURKA, CCNE2, ERBB2, and FGFR2, and loss of ER expression. In vitro experiments confirmed that these alterations conferred CDK4/6i resistance. Cancer cells cultured to resistance with CDK4/6i also acquired RB1, KRAS, AURKA, or CCNE2 alterations, which conferred sensitivity to AURKA, ERK, or CHEK1 inhibition. Three of these activating alterations-in AKT1, RAS, and AURKA-have not to our knowledge been previously demonstrated as mechanisms of resistance to CDK4/6 inhibitors in breast cancer preclinically or in patient samples. Together, these eight mechanisms were present in 66% of resistant tumors profiled and may define therapeutic opportunities in patients.
  2. Nat Commun. 2020 May 15. 11(1): 2416
    Saatci O, Kaymak A, Raza U, Ersan PG, Akbulut O, Banister CE, Sikirzhytski V, Tokat UM, Aykut G, Ansari SA, Dogan HT, Dogan M, Jandaghi P, Isik A, Gundogdu F, Kosemehmetoglu K, Dizdar O, Aksoy S, Akyol A, Uner A, Buckhaults PJ, Riazalhosseini Y, Sahin O.
      Chemoresistance is a major obstacle in triple negative breast cancer (TNBC), the most aggressive breast cancer subtype. Here we identify hypoxia-induced ECM re-modeler, lysyl oxidase (LOX) as a key inducer of chemoresistance by developing chemoresistant TNBC tumors in vivo and characterizing their transcriptomes by RNA-sequencing. Inhibiting LOX reduces collagen cross-linking and fibronectin assembly, increases drug penetration, and downregulates ITGA5/FN1 expression, resulting in inhibition of FAK/Src signaling, induction of apoptosis and re-sensitization to chemotherapy. Similarly, inhibiting FAK/Src results in chemosensitization. These effects are observed in 3D-cultured cell lines, tumor organoids, chemoresistant xenografts, syngeneic tumors and PDX models. Re-expressing the hypoxia-repressed miR-142-3p, which targets HIF1A, LOX and ITGA5, causes further suppression of the HIF-1α/LOX/ITGA5/FN1 axis. Notably, higher LOX, ITGA5, or FN1, or lower miR-142-3p levels are associated with shorter survival in chemotherapy-treated TNBC patients. These results provide strong pre-clinical rationale for developing and testing LOX inhibitors to overcome chemoresistance in TNBC patients.
  3. Cancer Metastasis Rev. 2020 May 12.
    Ferrer AI, Trinidad JR, Sandiford O, Etchegaray JP, Rameshwar P.
      Cancer remains one of the most challenging diseases despite significant advances of early diagnosis and therapeutic treatments. Cancerous tumors are composed of various cell types including cancer stem cells capable of self-renewal, proliferation, differentiation, and invasion of distal tumor sites. Most notably, these cells can enter a dormant cellular state that is resistant to conventional therapies. Thereby, cancer stem cells have the intrinsic potential for tumor initiation, tumor growth, metastasis, and tumor relapse after therapy. Both genetic and epigenetic alterations are attributed to the formation of multiple tumor types. This review is focused on how epigenetic dynamics involving DNA methylation and DNA oxidations are implicated in breast cancer and glioblastoma multiforme. The emergence and progression of these cancer types rely on cancer stem cells with the capacity to enter quiescence also known as a dormant cellular state, which dictates the distinct tumorigenic aggressiveness between breast cancer and glioblastomas.
    Keywords:  Bone marrow; Breast cancer; Cancer stem cells; Dormancy; Epigenetics; Glioblastoma multiforme; TET
  4. Cell Stem Cell. 2020 May 10. pii: S1934-5909(20)30144-2. [Epub ahead of print]
    Rothe K, Babaian A, Nakamichi N, Chen M, Chafe SC, Watanabe A, Forrest DL, Mager DL, Eaves CJ, Dedhar S, Jiang X.
      Patients with chronic myeloid leukemia (CML) often require lifelong therapy with ABL1 tyrosine kinase inhibitors (TKIs) due to a persisting TKI-resistant population of leukemic stem cells (LSCs). From transcriptome profiling, we show integrin-linked kinase (ILK), a key constituent of focal adhesions, is highly expressed in TKI-nonresponsive patient cells and their LSCs. Genetic and pharmacological inhibition of ILK impaired the survival of nonresponder patient cells, sensitizing them to TKIs, even in the presence of protective niche cells. Furthermore, ILK inhibition eliminated TKI-refractory LSCs from patients, but not normal HSCs, in vitro and in vivo. RNA-sequencing and functional validation studies implicated an important role of ILK in maintaining a requisite level of mitochondrial oxidative metabolism in highly purified, quiescent LSCs. Thus, these findings point to ILK as a critical survival mediator to TKIs and quiescent stem cells, offering an attractive therapeutic target and model for curative combination therapies in stem-cell-driven cancers.
    Keywords:  bone marrow niche; chronic myeloid leukemia; focal adhesions; integrin-linked kinase; leukemic stem cells; oxidative phosphorylation; quiescence; reactive oxygen species; therapy resistance; tyrosine kinase inhibitors
  5. Cell Stem Cell. 2020 May 10. pii: S1934-5909(20)30151-X. [Epub ahead of print]
    Morral C, Stanisavljevic J, Hernando-Momblona X, Mereu E, Álvarez-Varela A, Cortina C, Stork D, Slebe F, Turon G, Whissell G, Sevillano M, Merlos-Suárez A, Casanova-Martí À, Moutinho C, Lowe SW, Dow LE, Villanueva A, Sancho E, Heyn H, Batlle E.
      Colorectal cancers (CRCs) are composed of an amalgam of cells with distinct genotypes and phenotypes. Here, we reveal a previously unappreciated heterogeneity in the biosynthetic capacities of CRC cells. We discover that the majority of ribosomal DNA transcription and protein synthesis in CRCs occurs in a limited subset of tumor cells that localize in defined niches. The rest of the tumor cells undergo an irreversible loss of their biosynthetic capacities as a consequence of differentiation. Cancer cells within the biosynthetic domains are characterized by elevated levels of the RNA polymerase I subunit A (POLR1A). Genetic ablation of POLR1A-high cell population imposes an irreversible growth arrest on CRCs. We show that elevated biosynthesis defines stemness in both LGR5+ and LGR5- tumor cells. Therefore, a common architecture in CRCs is a simple cell hierarchy based on the differential capacity to transcribe ribosomal DNA and synthesize proteins.
    Keywords:  CRC; Cancer Stem Cell; biosynthetic capacity; plasticity; stem cell hierarchy
  6. Nat Commun. 2020 May 11. 11(1): 2350
    Ge JY, Shu S, Kwon M, Jovanović B, Murphy K, Gulvady A, Fassl A, Trinh A, Kuang Y, Heavey GA, Luoma A, Paweletz C, Thorner AR, Wucherpfennig KW, Qi J, Brown M, Sicinski P, McDonald TO, Pellman D, Michor F, Polyak K.
      BET inhibitors are promising therapeutic agents for the treatment of triple-negative breast cancer (TNBC), but the rapid emergence of resistance necessitates investigation of combination therapies and their effects on tumor evolution. Here, we show that palbociclib, a CDK4/6 inhibitor, and paclitaxel, a microtubule inhibitor, synergize with the BET inhibitor JQ1 in TNBC lines. High-complexity DNA barcoding and mathematical modeling indicate a high rate of de novo acquired resistance to these drugs relative to pre-existing resistance. We demonstrate that the combination of JQ1 and palbociclib induces cell division errors, which can increase the chance of developing aneuploidy. Characterizing acquired resistance to combination treatment at a single cell level shows heterogeneous mechanisms including activation of G1-S and senescence pathways. Our results establish a rationale for further investigation of combined BET and CDK4/6 inhibition in TNBC and suggest novel mechanisms of action for these drugs and new vulnerabilities in cells after emergence of resistance.
  7. Mol Cancer. 2020 May 13. 19(1): 90
    Zhang T, Qu R, Chan S, Lai M, Tong L, Feng F, Chen H, Song T, Song P, Bai G, Liu Y, Wang Y, Li Y, Su Y, Shen Y, Sun Y, Chen Y, Geng M, Ding K, Ding J, Xie H.
      BACKGROUND: Non-small cell lung cancer (NSCLC) patients with activating EGFR mutations initially respond to first-generation EGFR inhibitors; however, the efficacy of these drugs is limited by acquired resistance driven by the EGFR T790M mutation. The discovery of third-generation EGFR inhibitors overcoming EGFR T790M and their new resistance mechanisms have attracted much attention.METHODS: We examined the antitumor activities and potential resistance mechanism of a novel EGFR third-generation inhibitor in vitro and in vivo using ELISA, SRB assay, immunoblotting, flow cytometric analysis, kinase array, qRT-PCR and tumor xenograft models. The clinical effect on a patient was evaluated by computed tomography scan.
    RESULTS: We identified compound ASK120067 as a novel inhibitor of EGFR T790M, with selectivity over EGFR WT. ASK120067 exhibited potent anti-proliferation activity in tumor cells harboring EGFR T790M (NCI-H1975) and sensitizing mutations (PC-9 and HCC827) while showed moderate or weak inhibition in cells expressing EGFR WT. Oral administration of ASK120067 induced tumor regression in NSCLC xenograft models and in a PDX model harboring EGFR T790M. The treatment of one patient with advanced EGFR T790M-positive NSCLC was described as proof of principle. Moreover, we found that hyperphosphorylation of Ack1 and the subsequent activation of antiapoptotic signaling via the AKT pathway contributed to ASK120067 resistance. Concomitant targeting of EGFR and Ack1 effectively overrode the acquired resistance of ASK120067 both in vitro and in vivo.
    CONCLUSIONS: Our results idenfity ASK120067 as a promising third-generation EGFR inhibitor and reveal for the first time that Ack1 activation as a novel resistance mechanism to EGFR inhibitors that guide to potential combination strategy.
    Keywords:  Ack1; Drug resistance; EGFR T790M; Non-small cell lung cancer (NSCLC); Small-molecule inhibitor
  8. Blood. 2020 May 12. pii: blood.2019003124. [Epub ahead of print]
    Gebru MT, Atkinson JM, Young M, Zhang L, Tang Z, Liu Z, Lu P, Dower C, Chen L, Annageldiyev C, Sharma A, Kawasawa Y, Zhao Z, Miller BA, Claxton D, Wang HG.
      FLT3 is a frequently mutated gene that is highly associated with a poor prognosis in acute myeloid leukemia (AML). Despite initially responding to FLT3 inhibitors, most patients eventually relapse with drug-resistance. The mechanism by which resistance arises and the initial response to drug treatment that promotes cell survival is unknown. Recent studies show that a transiently maintained sub-population of drug-sensitive cells, so-called drug-tolerant persisters (DTPs), can survive cytotoxic drug exposure despite lacking resistance-conferring mutations. Using RNA-sequencing and drug-screening, here we report that treatment of FLT3-ITD AML cells with quizartinib, a selective FLT3 inhibitor, up-regulates inflammatory genes in DTPs and thereby confers susceptibility to anti-inflammatory glucocorticoids. Mechanistically, the combination of FLT3 inhibitors and glucocorticoids enhances cell death of FLT3 mutant but not wild-type cells through glucocorticoid receptor-dependent upregulation of the pro-apoptotic protein BIM and proteasomal degradation of the anti-apoptotic protein MCL-1. Moreover, the enhanced anti-leukemic activity by quizartinib and dexamethasone combination has been validated using primary AML patient samples and xenograft mouse models. Collectively, our study indicates that the combination of FLT3 inhibitors and glucocorticoids has the potential to eliminate DTPs and therefore prevent minimal residual disease, mutational drug resistance, and relapse in FLT3 mutant AML.
  9. Mol Cancer. 2020 May 09. 19(1): 86
    Luo Z, Rong Z, Zhang J, Zhu Z, Yu Z, Li T, Fu Z, Qiu Z, Huang C.
      BACKGROUND: As a novel type of noncoding RNAs, covalently closed circular RNAs (circRNAs) are ubiquitously expressed in eukaryotes. Emerging studies have related dysregulation of circRNAs to tumorigenesis. However, the biogenesis, regulation, function and mechanism of circRNAs in gastric cancer (GC) remain largely unclear.METHODS: The expression profile of circRNAs in 6 pairs of GC tissues and adjacent non-tumor tissues was analyzed by RNA-sequencing. Quantitative real-time PCR was used to determine the expression level of circCCDC9 in GC tissues and cell lines. Then, functional experiments in vitro and in vivo were employed to explore the effects of circCCDC9 on tumor growth and metastasis in GC. Mechanistically, dual luciferase reporter, fluorescence in situ hybridization (FISH), RNA immunoprecipitation (RIP) and RNA pull-down assays were performed to confirm that circCCDC9 directly sponged miR-6792-3p and alleviated suppression on target CAV1 expression.
    RESULTS: Evidently down-regulated expression of circCCDC9 was observed in both GC tissues and cell lines. Expression of circCCDC9 was negatively correlated with tumor size, lymph node invasion, advanced clinical stage and overall survival in GC patients. Functionally, overexpression of circCCDC9 significantly inhibited the proliferation, migration and invasion of GC cell lines in vitro and tumor growth and metastasis in vivo, whereas miR-6792-3p mimics counteracted these effects. Mechanistic analysis demonstrated that circCCDC9 acted as a "ceRNA" of miR-6792-3p to relieve the repressive effect of miR-6792-3p on its target CAV1, then suppressed the tumorigenesis of GC.
    CONCLUSIONS: CircCCDC9 functions as a tumor suppressor in inhibiting the progression of GC through miR-6792-3p/CAV1 axis, which has provided an exploitable biomarker and therapeutic target for patients with GC.
    Keywords:  CAV1; CircCCDC9; Gastric Cancer; miR-6792-3p
  10. Nat Commun. 2020 May 14. 11(1): 2393
    Vander Velde R, Yoon N, Marusyk V, Durmaz A, Dhawan A, Miroshnychenko D, Lozano-Peral D, Desai B, Balynska O, Poleszhuk J, Kenian L, Teng M, Abazeed M, Mian O, Tan AC, Haura E, Scott J, Marusyk A.
      Despite high initial efficacy, targeted therapies eventually fail in advanced cancers, as tumors develop resistance and relapse. In contrast to the substantial body of research on the molecular mechanisms of resistance, understanding of how resistance evolves remains limited. Using an experimental model of ALK positive NSCLC, we explored the evolution of resistance to different clinical ALK inhibitors. We found that resistance can originate from heterogeneous, weakly resistant subpopulations with variable sensitivity to different ALK inhibitors. Instead of the commonly assumed stochastic single hit (epi) mutational transition, or drug-induced reprogramming, we found evidence for a hybrid scenario involving the gradual, multifactorial adaptation to the inhibitors through acquisition of multiple cooperating genetic and epigenetic adaptive changes. Additionally, we found that during this adaptation tumor cells might present unique, temporally restricted collateral sensitivities, absent in therapy naïve or fully resistant cells, suggesting the potential for new therapeutic interventions, directed against evolving resistance.
  11. Oncogene. 2020 May 12.
    Zhu Z, Song J, Guo Y, Huang Z, Chen X, Dang X, Huang Y, Wang Y, Ou W, Yang Y, Yu W, Liu CY, Cui L.
      Aberrant expression of laminin-332 promotes tumour growth and metastasis in multiple cancers. However, the dysregulated expression and mechanism of action of LAMB3, which encodes the β3 subunit of laminin-332, and the mechanism underlying dysregulated LAMB3 expression in CRC remain obscure. Here, we show that LAMB3 is overexpressed in CRC and that this overexpression is correlated with tumour metastasis and poor prognosis. Overexpression of LAMB3 promoted cell proliferation and cell migration in vitro and tumour growth and metastasis in vivo, while knockdown of LAMB3 elicited opposing effects. LAMB3 inhibited the tumour suppressive function of FOXO3/4 by activating AKT in CRC. Both the BET inhibitor JQ1 and the MEK inhibitor U0126 decreased the mRNA level of LAMB3 in multiple CRC cells. Mechanistically, ELK4 cooperated with BRD2 to regulate the transcription of LAMB3 in CRC by directly binding to the ETS binding motifs in the LAMB3 promoter. ELK4 was as acetylated at K125, which enhanced the interaction between ELK4 and BRD2. JQ1 disrupted the interaction between ELK4 and BRD2, resulting in decreased binding of BRD2 to the LAMB3 promoter and downregulation of LAMB3 transcription. Both ELK4 and BRD2 expression was associated with LAMB3 expression in CRC. LAMB3 expression was also negatively correlated with FOXO3/4 in CRC. Our study reveals the pro-tumorigenic role of LAMB3 through the AKT-FOXO3/4 axis and the transcriptional mechanism of LAMB3 in CRC, demonstrating that LAMB3 is a potential therapeutic target that can be targeted by BET inhibitors and MEK inhibitors.
  12. Cell Res. 2020 May 12.
    Cui Y, Chen H, Xi R, Cui H, Zhao Y, Xu E, Yan T, Lu X, Huang F, Kong P, Li Y, Zhu X, Wang J, Zhu W, Wang J, Ma Y, Zhou Y, Guo S, Zhang L, Liu Y, Wang B, Xi Y, Sun R, Yu X, Zhai Y, Wang F, Yang J, Yang B, Cheng C, Liu J, Song B, Li H, Wang Y, Zhang Y, Cheng X, Zhan Q, Li Y, Liu Z.
      Esophageal squamous cell carcinoma (ESCC) is a poor-prognosis cancer type with limited understanding of its molecular etiology. Using 508 ESCC genomes, we identified five novel significantly mutated genes and uncovered mutational signature clusters associated with metastasis and patients' outcomes. Several functional assays implicated that NFE2L2 may act as a tumor suppressor in ESCC and that mutations in NFE2L2 probably impaired its tumor-suppressive function, or even conferred oncogenic activities. Additionally, we found that the NFE2L2 mutations were significantly associated with worse prognosis of ESCC. We also identified potential noncoding driver mutations including hotspot mutations in the promoter region of SLC35E2 that were correlated with worse survival. Approximately 5.9% and 15.2% of patients had high tumor mutation burden or actionable mutations, respectively, and may benefit from immunotherapy or targeted therapies. We found clinically relevant coding and noncoding genomic alterations and revealed three major subtypes that robustly predicted patients' outcomes. Collectively, we report the largest dataset of genomic profiling of ESCC useful for developing ESCC-specific biomarkers for diagnosis and treatment.
  13. Nat Commun. 2020 May 11. 11(1): 2333
    Nakayama M, Hong CP, Oshima H, Sakai E, Kim SJ, Oshima M.
      Missense-type mutant p53 plays a tumor-promoting role through gain-of-function (GOF) mechanism. In addition, the loss of wild-type TP53 through loss of heterozygosity (LOH) is widely found in cancer cells. However, malignant progression induced by cooperation of TP53 GOF mutation and LOH remains poorly understood. Here, we show that mouse intestinal tumors carrying Trp53 GOF mutation with LOH (AKTPM/LOH) are enriched in metastatic lesions when heterozygous Trp53 mutant cells (AKTP+/M) are transplanted. We show that Trp53 LOH is required for dormant cell survival and clonal expansion of cancer cells. Moreover, AKTPM/LOH cells show an increased in vivo tumor-initiating ability compared with AKTPNull and AKTP+/M cells. RNAseq analyses reveal that inflammatory and growth factor/MAPK pathways are specifically activated in AKTPM/LOH cells, while the stem cell signature is upregulated in both AKTPM/LOH and AKTPNull cells. These results indicate that TP53/Trp53 LOH promotes TP53/Trp53 GOF mutation-driven metastasis through the activation of distinct pathway combination.
  14. Oncogene. 2020 May 14.
    Meyer-Schaller N, Tiede S, Ivanek R, Diepenbruck M, Christofori G.
      An epithelial to mesenchymal transition (EMT) is an embryonic dedifferentiation program which is aberrantly activated in cancer cells to acquire cellular plasticity. This plasticity increases the ability of breast cancer cells to invade into surrounding tissue, to seed metastasis at distant sites and to resist to chemotherapy. In this study, we have observed a higher expression of interferon-related factors in basal-like and claudin-low subtypes of breast cancer in patients, known to be associated with EMT. Notably, Irf1 exerts essential functions during the EMT process, yet it is also required for the maintenance of an epithelial differentiation status of mammary gland epithelial cells: RNAi-mediated ablation of Irf1 in mammary epithelial cells results in the expression of mesenchymal factors and Smad transcriptional activity. Conversely, ablation of Irf1 during TGFβ-induced EMT prevents a mesenchymal transition and stabilizes the expression of E-cadherin. In the basal-like murine breast cancer cell line 4T1, RNAi-mediated ablation of Irf1 reduces colony formation and cell migration in vitro and shedding of circulating tumor cells and metastasis formation in vivo. This context-dependent dual role of Irf1 in the regulation of epithelial-mesenchymal plasticity provides important new insights into the functional contribution and therapeutic potential of interferon-regulated factors in breast cancer.
  15. Mol Cancer. 2020 May 11. 19(1): 87
    Jin X, Ge LP, Li DQ, Shao ZM, Di GH, Xu XE, Jiang YZ.
      BACKGROUND: Estrogen receptor-positive (ER+) breast cancers represent approximately two-thirds of all breast cancers and have a sustained risk of late disease recurrence. Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors have shown significant efficacy in ER+ breast cancer. However, their effects are still limited by drug resistance. In this study, we aim to explore the role of long noncoding RNA TROJAN in ER+ breast cancer.METHODS: The expression level of TROJAN in breast cancer tissue and cell lines was determined by quantitative real-time PCR. In vitro and in vivo assays as well as patient derived organoid were preformed to explore the phenotype of TROJAN in ER+ breast cancer. The TROJAN-NKRF-CDK2 axis were screened and validated by RNA pull-down, mass spectrometry, RNA immunoprecipitation, microarray, dual-luciferase reporter and chromatin immunoprecipitation assays.
    RESULTS: Herein, we showed that TROJAN was highly expressed in ER+ breast cancer. TROJAN promoted cell proliferation and resistance to a CDK4/6 inhibitor and was associated with poor survival in ER+ breast cancer. TROJAN can bind to NKRF and inhibit its interaction with RELA, upregulating the expression of CDK2. The inhibition of TROJAN abolished the activity of CDK2, reversing the resistance to CDK4/6 inhibitor. A TROJAN antisense oligonucleotide sensitized breast cancer cells and organoid to the CDK4/6 inhibitor palbociclib both in vitro and in vivo.
    CONCLUSIONS: TROJAN promotes ER+ breast cancer proliferation and is a potential target for reversing CDK4/6 inhibitor resistance.
    Keywords:  Breast cancer; CDK4/6 inhibitor; lncRNA TROJAN
  16. Leukemia. 2020 May 14.
    Patel AB, Pomicter AD, Yan D, Eiring AM, Antelope O, Schumacher JA, Kelley TW, Tantravahi SK, Kovacsovics TJ, Shami PJ, O'Hare T, Deininger MW.
      FLT3-ITD mutations occur in 20-30% of AML patients and are associated with aggressive disease. Patients with relapsed FLT3-mutated disease respond well to 2nd generation FLT3 TKIs but inevitably relapse within a short timeframe. In this setting, until overt relapse occurs, the bone marrow microenvironment facilitates leukemia cell survival despite continued on-target inhibition. We demonstrate that human bone marrow derived conditioned medium (CM) protects FLT3-ITD+ AML cells from the 2nd generation FLT3 TKI quizartinib and activates STAT3 and STAT5 in leukemia cells. Extrinsic activation of STAT5 by CM is the primary mediator of leukemia cell resistance to FLT3 inhibition. Combination treatment with quizartinib and dasatinib abolishes STAT5 activation and significantly reduces the IC50 of quizartinib in FLT3-ITD+ AML cells cultured in CM. We demonstrate that CM protects FLT3-ITD+ AML cells from the inhibitory effects of quizartinib on glycolysis and that this is partially reversed by treating cells with the combination of quizartinib and dasatinib. Using a doxycycline-inducible STAT5 knockdown in the FLT3-ITD+ MOLM-13 cell line, we show that dasatinib-mediated suppression of leukemia cell glycolytic activity is STAT5-independent and provide a preclinical rationale for combination treatment with quizartinib and dasatinib in FLT3-ITD+ AML.
  17. EMBO Mol Med. 2020 May 13. e11217
    Lahiguera Á, Hyroššová P, Figueras A, Garzón D, Moreno R, Soto-Cerrato V, McNeish I, Serra V, Lazaro C, Barretina P, Brunet J, Menéndez J, Matias-Guiu X, Vidal A, Villanueva A, Taylor-Harding B, Tanaka H, Orsulic S, Junza A, Yanes O, Muñoz-Pinedo C, Palomero L, Pujana MÀ, Perales JC, Viñals F.
      Mitochondrial metabolism and the generation of reactive oxygen species (ROS) contribute to the acquisition of DNA mutations and genomic instability in cancer. How genomic instability influences the metabolic capacity of cancer cells is nevertheless poorly understood. Here, we show that homologous recombination-defective (HRD) cancers rely on oxidative metabolism to supply NAD+ and ATP for poly(ADP-ribose) polymerase (PARP)-dependent DNA repair mechanisms. Studies in breast and ovarian cancer HRD models depict a metabolic shift that includes enhanced expression of the oxidative phosphorylation (OXPHOS) pathway and its key components and a decline in the glycolytic Warburg phenotype. Hence, HRD cells are more sensitive to metformin and NAD+ concentration changes. On the other hand, shifting from an OXPHOS to a highly glycolytic metabolism interferes with the sensitivity to PARP inhibitors (PARPi) in these HRD cells. This feature is associated with a weak response to PARP inhibition in patient-derived xenografts, emerging as a new mechanism to determine PARPi sensitivity. This study shows a mechanistic link between two major cancer hallmarks, which in turn suggests novel possibilities for specifically treating HRD cancers with OXPHOS inhibitors.
    Keywords:   BCRA ; OXPHOS ; PARP inhibitors; cancer metabolism; metformin
  18. Proc Natl Acad Sci U S A. 2020 May 14. pii: 201921531. [Epub ahead of print]
    Rajesh Y, Biswas A, Kumar U, Banerjee I, Das S, Maji S, Das SK, Emdad L, Cavenee WK, Mandal M, Fisher PB.
      Glioblastoma multiforme (GBM) is an aggressive cancer without currently effective therapies. Radiation and temozolomide (radio/TMZ) resistance are major contributors to cancer recurrence and failed GBM therapy. Heat shock proteins (HSPs), through regulation of extracellular matrix (ECM) remodeling and epithelial mesenchymal transition (EMT), provide mechanistic pathways contributing to the development of GBM and radio/TMZ-resistant GBM. The Friend leukemia integration 1 (Fli-1) signaling network has been implicated in oncogenesis in GBM, making it an appealing target for advancing novel therapeutics. Fli-1 is linked to oncogenic transformation with up-regulation in radio/TMZ-resistant GBM, transcriptionally regulating HSPB1. This link led us to search for targeted molecules that inhibit Fli-1. Expression screening for Fli-1 inhibitors identified lumefantrine, an antimalarial drug, as a probable Fli-1 inhibitor. Docking and isothermal calorimetry titration confirmed interaction between lumefantrine and Fli-1. Lumefantrine promoted growth suppression and apoptosis in vitro in parental and radio/TMZ-resistant GBM and inhibited tumor growth without toxicity in vivo in U87MG GBM and radio/TMZ-resistant GBM orthotopic tumor models. These data reveal that lumefantrine, an FDA-approved drug, represents a potential GBM therapeutic that functions through inhibition of the Fli-1/HSPB1/EMT/ECM remodeling protein networks.
    Keywords:  Fli-1; HSPB1; TMZ resistance; glioblastoma; radioresistance
  19. Nat Commun. 2020 May 11. 11(1): 2345
    Su Y, Ko ME, Cheng H, Zhu R, Xue M, Wang J, Lee JW, Frankiw L, Xu A, Wong S, Robert L, Takata K, Yuan D, Lu Y, Huang S, Ribas A, Levine R, Nolan GP, Wei W, Plevritis SK, Li G, Baltimore D, Heath JR.
      The determination of individual cell trajectories through a high-dimensional cell-state space is an outstanding challenge for understanding biological changes ranging from cellular differentiation to epigenetic responses of diseased cells upon drugging. We integrate experiments and theory to determine the trajectories that single BRAFV600E mutant melanoma cancer cells take between drug-naive and drug-tolerant states. Although single-cell omics tools can yield snapshots of the cell-state landscape, the determination of individual cell trajectories through that space can be confounded by stochastic cell-state switching. We assayed for a panel of signaling, phenotypic, and metabolic regulators at points across 5 days of drug treatment to uncover a cell-state landscape with two paths connecting drug-naive and drug-tolerant states. The trajectory a given cell takes depends upon the drug-naive level of a lineage-restricted transcription factor. Each trajectory exhibits unique druggable susceptibilities, thus updating the paradigm of adaptive resistance development in an isogenic cell population.
  20. Elife. 2020 May 15. pii: e57678. [Epub ahead of print]9
    Bley N.
      Mutations that allow tumors to evolve and become resistant to treatment can be readily identified with a new sequencing approach.
    Keywords:  cancer biology; genetics; genomics; human; machine learning; tumor evolution; variant calling
  21. Mol Cancer. 2020 May 12. 19(1): 88
    Wang T, Kong S, Tao M, Ju S.
      N6-methyladenosine (m6A) is considered the most common, abundant, and conserved internal transcript modification, especially in eukaryotic messenger RNA (mRNA). m6A is installed by m6A methyltransferases (METTL3/14, WTAP, RBM15/15B, VIRMA and ZC3H13, termed "writers"), removed by demethylases (FTO, ALKBH5, and ALKBH3, termed "erasers"), and recognized by m6A-binding proteins (YTHDC1/2, YTHDF1/2/3, IGF2BP1/2/3, HNRNP, and eIF3, termed "readers"). Accumulating evidence suggests that m6A RNA methylation greatly impacts RNA metabolism and is involved in the pathogenesis of many kinds of diseases, including cancers. In this review, we focus on the physiological functions of m6A modification and its related regulators, as well as on the potential biological roles of these elements in human tumors.
    Keywords:  Cancer progression; Molecular mechanisms; N6-methyladenosine (m6A)
  22. Nat Med. 2020 May;26(5): 693-698
    Yuen KC, Liu LF, Gupta V, Madireddi S, Keerthivasan S, Li C, Rishipathak D, Williams P, Kadel EE, Koeppen H, Chen YJ, Modrusan Z, Grogan JL, Banchereau R, Leng N, Thastrom A, Shen X, Hashimoto K, Tayama D, van der Heijden MS, Rosenberg JE, McDermott DF, Powles T, Hegde PS, Huseni MA, Mariathasan S.
      Although elevated plasma interleukin-8 (pIL-8) has been associated with poor outcome to immune checkpoint blockade 1, this has not been comprehensively evaluated in large randomized studies. Here we analyzed circulating pIL-8 and IL8 gene expression in peripheral blood mononuclear cells and tumors of patients treated with atezolizumab (anti-PD-L1 monoclonal antibody) from multiple randomized trials representing 1,445 patients with metastatic urothelial carcinoma (mUC) and metastatic renal cell carcinoma. High levels of IL-8 in plasma, peripheral blood mononuclear cells and tumors were associated with decreased efficacy of atezolizumab in patients with mUC and metastatic renal cell carcinoma, even in tumors that were classically CD8+ T cell inflamed. Low baseline pIL-8 in patients with mUC was associated with increased response to atezolizumab and chemotherapy. Patients with mUC who experienced on-treatment decreases in pIL-8 exhibited improved overall survival when treated with atezolizumab but not with chemotherapy. Single-cell RNA sequencing of the immune compartment showed that IL8 is primarily expressed in circulating and intratumoral myeloid cells and that high IL8 expression is associated with downregulation of the antigen-presentation machinery. Therapies that can reverse the impacts of IL-8-mediated myeloid inflammation will be essential for improving outcomes of patients treated with immune checkpoint inhibitors.
  23. J Clin Invest. 2020 May 12. pii: 134930. [Epub ahead of print]
    Li M, Fan L, Han D, Yu Z, Ma J, Liu Y, Li P, Zhao D, Chai J, Jiang L, Li S, Xiao J, Duan Q, Ye J, Shi M, Nie Y, Wu KC, Liao DJ, Shi Y, Wang Y, Yan Q, Guo S, Bian XW, Zhu F, Zhang J, Wang Z.
      Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive cancers and is highly resistant to current treatments. ESCC harbors a subpopulation of cells exhibiting cancer stem-like cell (CSC) properties that contribute to therapeutic resistance including radioresistance, but the molecular mechanisms in ESCC CSCs are currently unknown. Here, we report that ribosomal S6 protein kinase 4 (RSK4) plays a pivotal role in promoting CSC properties and radioresistance in ESCC. RSK4 was highly expressed in ESCC CSCs and associated with radioresistance and poor survival in ESCC patients. RSK4 was found to be a direct downstream transcriptional target of ΔNp63α, the main p63 isoform, which is frequently amplified in ESCC. RSK4 activated the β-catenin signaling pathway through direct phosphorylation of GSK-3β Ser9. Pharmacologic inhibition of RSK4 effectively reduced CSC properties and improves radiosensitivity in both nude mice and patient-derived xenograft models. Collectively, our results strongly suggest that the ΔNp63α-RSK4-GSK-3β axis plays a key role in driving CSC properties and radioresistance in ESCC, indicating that RSK4 is a promising therapeutic target for ESCC treatment.
    Keywords:  Cancer; Oncology
  24. Nat Rev Clin Oncol. 2020 May 12.
    Ho WJ, Jaffee EM, Zheng L.
      Metastatic pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid tumours despite the use of multi-agent conventional chemotherapy regimens. Such poor outcomes have fuelled ongoing efforts to exploit the tumour microenvironment (TME) for therapy, but strategies aimed at deconstructing the surrounding desmoplastic stroma and targeting the immunosuppressive pathways have largely failed. In fact, evidence has now shown that the stroma is multi-faceted, which illustrates the complexity of exploring features of the TME as isolated targets. In this Review, we describe ways in which the PDAC microenvironment has been targeted and note the current understanding of the clinical outcomes that have unexpectedly contradicted preclinical observations. We also consider the more sophisticated therapeutic strategies under active investigation - multi-modal treatment approaches and exploitation of biologically integrated targets - which aim to remodel the TME against PDAC.
  25. Cancer Res. 2020 May 14. pii: canres.0079.2020. [Epub ahead of print]
    Morris AH, Orbach SM, Bushnell GG, Oakes RS, Jeruss JS, Shea LD.
      Cancer metastasis poses a challenging problem both clinically and scientifically, as the stochastic nature of metastatic lesion formation introduces complexity for both early detection and the study of metastasis in preclinical models. Engineered metastatic niches represent an emerging approach to address this stochasticity by creating bioengineered sites where cancer can preferentially metastasize. As the engineered niche captures the earliest metastatic cells at a non-vital location, both non-invasive and biopsy-based monitoring of these sites can be performed routinely to detect metastasis early and monitor alterations in the forming metastatic niche. The engineered metastatic niche also provides a new platform technology that serves as a tunable site to molecularly dissect metastatic disease mechanisms. Ultimately, linking the engineered niches with advances in sensor development and synthetic biology can provide enabling tools for preclinical cancer models and fosters the potential to impact the future of clinical cancer care.
  26. EMBO Mol Med. 2020 May 13. e12355
    Khan KA, Kerbel RS.
      Targeting the metastatic process is a critical pursuit in the treatment of malignant disease. There are currently no specific anti-metastatic drugs approved for clinical use, despite metastasis being the leading cause of death for cancer patients. Targeting the Tie1 receptor was shown as a possible strategy for selective anti-metastasis therapies based on previous gene deletion studies. This current study is the first description of a human antibody against Tie1 with the potential for clinical use in targeting extravasation of tumor cells into organs such as the lung, without having a detrimental effect on immune cell infiltration.
  27. Clin Cancer Res. 2020 May 12. pii: clincanres.0056.2020. [Epub ahead of print]
    Lampert EJ, Zimmer AS, Padget MR, Cimino-Mathews A, Nair JR, Liu Y, Swisher EM, Hodge JW, Nixon AB, Nichols E, Bagheri M, Levy E, Radke MR, Lipkowitz S, Annunziata CM, Taube JM, Steinberg SM, Lee JM.
      PURPOSE: Preclinical studies suggest PARP inhibition (PARPi) induces immunostimulatory micromilieu in ovarian cancer thus complementing activity of immune checkpoint blockade. We conducted a phase 2 trial of PARPi olaparib and anti-PD-L1 durvalumab and collected paired fresh core biopsies and blood samples to test this hypothesis.EXPERIMENTAL DESIGN: In a single-center, proof-of-concept phase 2 study, we enrolled women aged ≥18 with recurrent ovarian cancer. All patients were immune-checkpoint inhibitor naïve and had measurable disease per RECISTv1.1, ECOG performance status 0-2, and adequate organ and marrow function. Patients received olaparib 300mg twice daily and durvalumab 1500mg intravenously every 4 weeks until disease progression, unacceptable toxicity, or withdrawal of consent. Primary endpoint was overall response rate (ORR). Secondary objectives were safety and progression-free survival (PFS). Translational objectives included biomarker evaluation for relationships with clinical response and immunomodulatory effects by treatment.
    RESULTS: 35 ovarian cancer patients (median 4 prior therapies [IQR 2-5.5], predominantly platinum-resistant [86%], BRCA wild-type [77%]) received at least one full cycle of treatment. ORR was 14% (5/35;95%CI,4.8%-30.3%). Disease control rate (PR+SD) was 71% (25/35;95%CI,53.7%-85.4%). Treatment enhanced IFNγ and CXCL9/CXCL10 expression, systemic IFNγ/TNFα production, and tumor-infiltrating lymphocytes, indicating an immunostimulatory environment. Increased IFNγ production was associated with improved PFS (HR:0.37[95%CI,0.16-0.87], p=0.023) while elevated VEGFR3 levels were associated with worse PFS (HR=3.22[95%CI,1.23-8.40], p=0.017).
    CONCLUSIONS: The PARPi and anti-PD-L1 combination showed modest clinical activity in recurrent ovarian cancer. Our correlative study results suggest immunomodulatory effects by olaparib/durvalumab in patients and indicate that VEGF/VEGFR pathway blockade would be necessary for improved efficacy of the combination.