bims-cadres 2022-08-28 papers

bims-cadres

Biomed News

on Cancer drug resistance

Issue of 2022‒08‒28
ten papers selected by
Rana Gbyli
Yale University

Reversal of Epithelial-Mesenchymal Transition and Inhibition of Tumor Stemness of Breast Cancer Cells Through Advanced Combined Chemotherapy.
Role of dual specificity phosphatases (DUSPs) in melanoma cellular plasticity and drug resistance.
DNA methylome and single-cell transcriptome analyses reveal CDA as a potential druggable target for ALK inhibitor-resistant lung cancer therapy.
Transposon-activated POU5F1B promotes colorectal cancer growth and metastasis.
PLEK2 promotes cancer stemness and tumorigenesis of head and neck squamous cell carcinoma via the c-Myc-mediated positive feedback loop.
T-Box transcription factor 2 enhances chemoresistance of endometrial cancer by mediating NRF2 expression.
Cancer Metabolism and Resistance to Cell Death: Novel Therapeutic Perspectives.
CRNDE acts as an epigenetic modulator of the p300/YY1 complex to promote HCC progression and therapeutic resistance.
Genomic Alterations to Guide Treatment Selection in Metastatic Prostate Cancer.
Targeting Histone Epigenetic Modifications and DNA Damage Responses in Synthetic Lethality Strategies in Cancer?

Acta Biomater. 2022 Aug 23. pii: S1742-7061(22)00501-3. [Epub ahead of print]

Reversal of Epithelial-Mesenchymal Transition and Inhibition of Tumor Stemness of Breast Cancer Cells Through Advanced Combined Chemotherapy.

Yani Cui, Mingda Zhao, Yuedi Yang, Ruiling Xu, Lei Tong, Jie Liang, Xingdong Zhang, Yong Sun, Yujiang Fan.

  The abnormal activation of the Wnt/β-catenin signaling pathway and epithelial-mesenchymal transition (EMT) in drug-resistant tumor cells and cancer stem cells (CSCs) stimulate tumor metastasis and recurrence. Here, a promising combined chemotherapeutic strategy of salinomycin (SL) and doxorubicin (DOX) with specific inhibition of tumor stemness by a targeted co-delivery nanosystem was developed to overcome this abnormal progression. This strategy could be benefit drugs to effectively penetrate and infiltrate into spheres of 3D-cultured breast cancer stem cells (BCSCs). The expression of the Wnt/β-catenin signaling pathway-related genes (β-catenin, LRP6, LEF1, and TCF12) and target genes (Cyclin D1, Cmyc, and Fibronectin) as well as CSC stemness-related genes (Oct4, Nanog, and Hes1) was downregulated by redox-sensitive co-delivery micelles decorated with oligohyaluronic acid as the active targeting moiety. The changes in EMT-associated gene expression (E-cadherin and Vimentin) in vitro showed that the EMT process was also effectively inverted. This strategy achieved a strong inhibitory effect on solid tumor growth and an effective reduction in the risk of tumor metastasis in 4T1 tumor-bearing mice in vivo and effectively alleviated splenomegaly caused by the malignant tumor. Immunohistochemical staining analysis of E-cadherin, Vimentin, and β-catenin confirmed that the inversion of the EMT was also achieved in solid tumors. These results highlight the potential of SL and DOX combined chemotherapeutic strategy for eliminating breast carcinoma. STATEMENT OF SIGNIFICANCE: Cancer stem cells (CSCs), as an important part of tumor heterogeneity, can survive against conventional chemotherapy and initiate tumorigenesis, recurrence, and metastasis. Moreover, non-CSCs can convert into the CSC state through the abnormal Wnt/β-catenin pathway, which is closely related to the epithelial-mesenchymal transition (EMT) process. Here, redox-degradable binary drug-loaded micelles (PPH/DOX+SL) were designed to target CSCs and overcome drug resistance of breast cancer cells. The combined chemotherapy of salinomycin (SL) and doxorubicin (DOX) reversed drug resistance, while the PPH/DOX+SL micelles enhanced the intracellular accumulation and drug penetration of BCSC spheres. The introduction of SL downregulated the expression of tumor stemness genes and the Wnt/β-catenin pathway-related genes and inverted the EMT process. PPH/DOX+SL continuously inhibited tumor growth and invasion in vivo.

Keywords:  Combined Chemotherapy; EMT; Salinomycin; Tumor Stemness; Wnt/β-catenin

DOI:  https://doi.org/10.1016/j.actbio.2022.08.024
Sci Rep. 2022 Aug 23. 12(1): 14395

Role of dual specificity phosphatases (DUSPs) in melanoma cellular plasticity and drug resistance.

Mithalesh K Singh, Sarah Altameemi, Marcos Lares, Michael A Newton, Vijayasaradhi Setaluri.

Melanoma cells exhibit phenotypic plasticity that allows transition from a proliferative and differentiated phenotype to a more invasive and undifferentiated or transdifferentiated phenotype often associated with drug resistance. The mechanisms that control melanoma phenotype plasticity and its role in drug resistance are not fully understood. We previously demonstrated that emergence of MAPK inhibitor (MAPKi)-resistance phenotype is associated with decreased expression of stem cell proliferation genes and increased expression of MAPK inactivation genes, including dual specificity phosphatases (DUSPs). Several members of the DUSP family genes, specifically DUSP1, -3, -8 and -9, are expressed in primary and metastatic melanoma cell lines and pre-and post BRAFi treated melanoma cells. Here, we show that knockdown of DUSP1 or DUSP8 or treatment with BCI, a pharmacological inhibitor of DUSP1/6 decrease the survival of MAPKi-resistant cells and sensitizes them to BRAFi and MEKi. Pharmacological inhibition of DUSP1/6 upregulated nestin, a neural crest stem cell marker, in both MAPKi-sensitive cells and cells with acquired MAPKi-resistance. In contrast, treatment with BCI resulted in upregulation of MAP2, a neuronal differentiation marker, only in MAPKi-sensitive cells but caused downregulation of both MAP2 and GFAP, a glial marker, in all MAPKi-resistant cell lines. These data suggest that DUSP proteins are involved in the regulation of cellular plasticity cells and melanoma drug resistance and are potential targets for treatment of MAPKi-resistant melanoma.

DOI: https://doi.org/10.1038/s41598-022-18578-x
Exp Mol Med. 2022 Aug 23.

DNA methylome and single-cell transcriptome analyses reveal CDA as a potential druggable target for ALK inhibitor-resistant lung cancer therapy.

Haejeong Heo, Jong-Hwan Kim, Hyun Jung Lim, Jeong-Hwan Kim, Miso Kim, Jaemoon Koh, Joo-Young Im, Bo-Kyung Kim, Misun Won, Ji-Hwan Park, Yang-Ji Shin, Mi Ran Yun, Byoung Chul Cho, Yong Sung Kim, Seon-Young Kim, Mirang Kim.

Acquired resistance to inhibitors of anaplastic lymphoma kinase (ALK) is a major clinical challenge for ALK fusion-positive non-small-cell lung cancer (NSCLC). In the absence of secondary ALK mutations, epigenetic reprogramming is one of the main mechanisms of drug resistance, as it leads to phenotype switching that occurs during the epithelial-to-mesenchymal transition (EMT). Although drug-induced epigenetic reprogramming is believed to alter the sensitivity of cancer cells to anticancer treatments, there is still much to learn about overcoming drug resistance. In this study, we used an in vitro model of ceritinib-resistant NSCLC and employed genome-wide DNA methylation analysis in combination with single-cell (sc) RNA-seq to identify cytidine deaminase (CDA), a pyrimidine salvage pathway enzyme, as a candidate drug target. CDA was hypomethylated and upregulated in ceritinib-resistant cells. CDA-overexpressing cells were rarely but definitively detected in the naïve cell population by scRNA-seq, and their abundance was increased in the acquired-resistance population. Knockdown of CDA had antiproliferative effects on resistant cells and reversed the EMT phenotype. Treatment with epigenome-related nucleosides such as 5-formyl-2'-deoxycytidine selectively ablated CDA-overexpressing resistant cells via accumulation of DNA damage. Collectively, our data suggest that targeting CDA metabolism using epigenome-related nucleosides represents a potential new therapeutic strategy for overcoming ALK inhibitor resistance in NSCLC.

DOI: https://doi.org/10.1038/s12276-022-00836-7
Nat Commun. 2022 Aug 20. 13(1): 4913

Transposon-activated POU5F1B promotes colorectal cancer growth and metastasis.

Laia Simó-Riudalbas, Sandra Offner, Evarist Planet, Julien Duc, Laurence Abrami, Sagane Dind, Alexandre Coudray, Mairene Coto-Llerena, Caner Ercan, Salvatore Piscuoglio, Claus Lindbjerg Andersen, Jesper Bertram Bramsen, Didier Trono.

The treatment of colorectal cancer (CRC) is an unmet medical need in absence of early diagnosis. Here, upon characterizing cancer-specific transposable element-driven transpochimeric gene transcripts (TcGTs) produced by this tumor in the SYSCOL cohort, we find that expression of the hominid-restricted retrogene POU5F1B through aberrant activation of a primate-specific endogenous retroviral promoter is a strong negative prognostic biomarker. Correlating this observation, we demonstrate that POU5F1B fosters the proliferation and metastatic potential of CRC cells. We further determine that POU5F1B, in spite of its phylogenetic relationship with the POU5F1/OCT4 transcription factor, is a membrane-enriched protein that associates with protein kinases and known targets or interactors as well as with cytoskeleton-related molecules, and induces intracellular signaling events and the release of trans-acting factors involved in cell growth and cell adhesion. As POU5F1B is an apparently non-essential gene only lowly expressed in normal tissues, and as POU5F1B-containing TcGTs are detected in other tumors besides CRC, our data provide interesting leads for the development of cancer therapies.

DOI: https://doi.org/10.1038/s41467-022-32649-7
Cancer Commun (Lond). 2022 Aug 24.

PLEK2 promotes cancer stemness and tumorigenesis of head and neck squamous cell carcinoma via the c-Myc-mediated positive feedback loop.

Xinyuan Zhao, Dalong Shu, Wenjuan Sun, Shanshan Si, Wei Ran, Bing Guo, Li Cui.

  BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is one of the most frequent malignancies worldwide and is characterized by unfavorable prognosis, high lymph node metastasis and early recurrence. However, the molecular events regulating HNSCC tumorigenesis remain poorly understood. Therefore, uncovering the underlying mechanisms is urgently needed to identify novel and promising therapeutic targets for HNSCC. In this study, we aimed to explore the role of pleckstrin-2 (PLEK2) in regulating HNSCC tumorigenesis.METHODS: The expression pattern of PLEK2 and its clinical significance in HNSCC were determined by analyzing publicly assessable datasets and our own independent HNSCC cohort. In vitro and in vivo experiments, including cell proliferation, colony formation, Matrigel invasion, tumor sphere formation, ALDEFLUOR, Western blotting assays and xenograft mouse models, were used to investigate the role of PLEK2 in regulating the malignant behaviors of HNSCC cells. The underlying molecular mechanisms for the tumor-promoting role of PLEK2 were elucidated using co-immunoprecipitation, cycloheximide chase analysis, ubiquitination assays, chromatin immunoprecipitation-quantitative polymerase chain reaction, luciferase reporter assays and rescue experiments.
RESULTS: The expression levels of PLEK2 mRNA and protein were significantly increased in HNSCC tissues, and PLEK2 overexpression was strongly associated with poor overall survival and therapeutic resistance. Additionally, PLEK2 was important for maintaining the proliferation, invasion, epithelial-mesenchymal transition, cancer stemness and tumorigenesis of HNSCC cells and could alter the cellular metabolism of the cancer cells. Mechanistically, PLEK2 interacted with c-Myc and reduced the association of F-box and WD repeat domain containing 7 (FBXW7) with c-Myc, thereby avoiding ubiquitination and subsequent proteasome-mediated degradation of c-Myc. Moreover, the c-Myc signaling activated by PLEK2 was important for sustaining the aggressive malignant phenotypes and tumorigenesis of HNSCC cells. c-Myc also directly bounded to the PLEK2 promoter and activated its transcription, forming a positive feedback loop.
CONCLUSIONS: Collectively, these findings uncover a previously unknown molecular basis of PLEK2-enhanced c-Myc signaling in HNSCC, suggesting that PLEK2 may represent a promising therapeutic target for treating HNSCC.

Keywords:  FBXW7; HNSCC; PLEK2; c-Myc; cancer stemness; positive feedback loop; tumorigenesis; ubiquitination-mediated degradation

DOI:  https://doi.org/10.1002/cac2.12349
Curr Protein Pept Sci. 2022 Aug 23.

T-Box transcription factor 2 enhances chemoresistance of endometrial cancer by mediating NRF2 expression.

Ning Ding, Ting Zhang, Xiaohui Yu, Shichao Zhuang.

  BACKGROUND: The roles of T-Box transcription factor (TBX2) in endometrial cancer are still not clear. This study was designed to explore the roles of TBX2 in endometrial cancer and the underlying mechanisms.METHODS: The knockdown and overexpression of TBX2 in endometrial cancer cell lines were constructed by using lentivirus transduction. The xenograft animal model was established by using stable endometrial cancer cell lines. Cell viability was determined by the CCK-8 assay. The mRNA and protein levels of target genes were determined by using qPCR and Western blotting, respectively. ChIP assay was used to determine the interactions between TBX2 and nuclear factor erythroid 2-related factor 2 (NRF2).
RESULTS: The upregulation of TBX2 was observed in endometrial cancer tissues from patients with Cisplatin-resistance and Cisplatin-resistant cells. Interestingly, TBX2 regulated cell viability and Cisplatin resistance of endometrial cancer cells. In addition, the regulatory effects of TBX2 on chemo-resistance of endometrial cancer cells were associated with the NRF2 signaling pathways. Consistently, the endometrial cancer xenograft animal model revealed that TBX2 regulated tumor growth and Cisplatin resistance, and its regulatory effects were in part by the regulation of NRF2 signaling pathways.
CONCLUSION: TBX 2 enhanced Cisplatin resistance of endometrial cancer by regulating the NRF2 signaling pathways.

Keywords:  Chemo-resistance; Cisplatin resistance; Endometrial cancer; NRF2; TBX2

DOI:  https://doi.org/10.2174/1389203723666220823152239
Biomedicines. 2022 Jul 29. pii: 1828. [Epub ahead of print]10(8):

Cancer Metabolism and Resistance to Cell Death: Novel Therapeutic Perspectives.

Francesco Ciccarese.

Deregulation of metabolism and resistance to cell death are two hallmarks of cancer [...].

DOI: https://doi.org/10.3390/biomedicines10081828
Clin Epigenetics. 2022 Aug 23. 14(1): 106

CRNDE acts as an epigenetic modulator of the p300/YY1 complex to promote HCC progression and therapeutic resistance.

Yu-Chin Liu, Yang-Hsiang Lin, Hsiang-Cheng Chi, Po-Shuan Huang, Chia-Jung Liao, Yu-Syuan Liou, Chiao-Chun Lin, Chia-Jung Yu, Chau-Ting Yeh, Ya-Hui Huang, Kwang-Huei Lin.

  BACKGROUND: Hepatocellular carcinoma (HCC) is one of the most common primary liver malignancies worldwide. The long-term prognosis for HCC remains extremely poor, with drug resistance being the major underlying cause of recurrence and mortality. The lncRNA colorectal neoplasia differentially expressed (CRNDE) is an epigenetic mediator and plays an important role to drive proliferation and drug resistance in HCC. However, CRNDE as an epigenetic regulator with influences sorafenib resistance in HCC is unclear. Thus, we explore the potential of targeting the CRNDE/p300/YY1 axis as a novel therapeutic strategy to overcome sorafenib resistance of HCC.METHOD: Detection of the expression level of CRNDE and EGFR in clinical specimens of HCC. CRNDE, EGFR, p300, and YY1expression were altered in HCC cells through transfection with different plasmids, and cell proliferation, migration, invasion, and sorafenib resistance were subsequently observed. Immunoprecipitation, chromatin immunoprecipitation, re-chromatin immunoprecipitation, site-directed mutagenesis, RNA Immunoprecipitation, immune fluorescence, qRT-PCR, and western blotting were performed to uncover the mechanisms of CRNDE regulation. The xenograft nude mice model was used to investigate the tumor growth and sorafenib resistance.
RESULTS: In this study, we showed that CRNDE expression is significantly positively correlated with that of epidermal growth factor receptor (EGFR) in clinical specimens of HCC and induces proliferation and sorafenib resistance of HCC via EGFR-mediated signaling. Mechanistically, CRNDE stabilized the p300/YY1 complex at the EGFR promoter and simultaneously enhanced histone H3K9 and H3K27 acetylation, which serve as markers of relaxed chromatin. EGFR was positively upregulated by the epigenetic complex, p300/YY1, in a manner dependent on CRNDE expression, leading to enhanced tumor cell proliferation and sorafenib resistance. Furthermore, C646, a p300 inhibitor, suppressed EGFR transcriptional activity by decreasing chromatin relaxation and YY1 binding, which effectively reduced proliferation/sorafenib resistance and prolonged overall survival.
CONCLUSION: Our collective findings support the potential of targeting the CRNDE/p300/YY1 axis as a novel therapeutic strategy to overcome sorafenib resistance of HCC.

Keywords:  C646; CRNDE; EGFR; H3K27Ac; H3K9Ac; Hepatocellular carcinoma (HCC); Sorafenib; p300

DOI:  https://doi.org/10.1186/s13148-022-01326-3
Crit Rev Oncog. 2022 ;27(1): 61-80

Genomic Alterations to Guide Treatment Selection in Metastatic Prostate Cancer.

Amy Davies, Arun A Azad, Edmond M Kwan.

Treatment options for men with metastatic prostate cancer have greatly expanded in the last decade. Androgen receptor pathway inhibitors, taxane cytotoxic therapy, poly(ADP-ribose) polymerase inhibitors, and radionuclide theranostics against prostate-specific membrane antigen have collectively contributed to incremental improvements in both quality and longevity of life for patients with metastatic castration-resistant prostate cancer (mCRPC). Despite these successes, few studies inform on optimal therapy selection and sequencing across this crowded treatment landscape. Genomic analysis of both tissue and liquid biopsy specimens shows promise in bridging this practice gap, with alterations in several key prostate cancer driver genes demonstrating clear associations with clinical outcomes, as well as informing use of novel precision medicine targeted therapies. In this review, we evaluate the current evidence of genomic alterations in various oncogenic signaling pathways as clinical biomarkers in mCRPC, focusing on correlative studies that analyzed outcomes based on findings in plasma cell-free DNA. We highlight the pitfalls of interpreting genomic findings in samples with substandard tumor content, and suggest pathologic and disease factors to consider when embarking upon tumor genotyping to guide treatment decisions in metastatic prostate cancer. As access to life-prolonging therapies improves, and barriers to cost-effective genotyping and reliable data interpretation are overcome, we anticipate that predictive and prognostic biomarkers that inform on disease biology, drug sensitivity, and therapy resistance will inevitably be integrated into the routine care of patients with metastatic prostate cancer.

DOI: https://doi.org/10.1615/CritRevOncog.2022043298
Cancers (Basel). 2022 Aug 22. pii: 4050. [Epub ahead of print]14(16):

Targeting Histone Epigenetic Modifications and DNA Damage Responses in Synthetic Lethality Strategies in Cancer?

Pedro A Lazo.

  Synthetic lethality strategies are likely to be integrated in effective and specific cancer treatments. These strategies combine different specific targets, either in similar or cooperating pathways. Chromatin remodeling underlies, directly or indirectly, all processes of tumor biology. In this context, the combined targeting of proteins associated with different aspects of chromatin remodeling can be exploited to find new alternative targets or to improve treatment for specific individual tumors or patients. There are two major types of proteins, epigenetic modifiers of histones and nuclear or chromatin kinases, all of which are druggable targets. Among epigenetic enzymes, there are four major families: histones acetylases, deacetylases, methylases and demethylases. All these enzymes are druggable. Among chromatin kinases are those associated with DNA damage responses, such as Aurora A/B, Haspin, ATM, ATR, DNA-PK and VRK1-a nucleosomal histone kinase. All these proteins converge on the dynamic regulation chromatin organization, and its functions condition the tumor cell viability. Therefore, the combined targeting of these epigenetic enzymes, in synthetic lethality strategies, can sensitize tumor cells to toxic DNA-damage-based treatments, reducing their toxicity and the selective pressure for tumor resistance and increasing their immunogenicity, which will lead to an improvement in disease-free survival and quality of life.

Keywords:  chromatin kinase; lysine acetylase; lysine deacetylase; lysine demethylase; lysine methylase

DOI:  https://doi.org/10.3390/cancers14164050