bims-cadres 2023-01-15 papers

bims-cadres

Biomed News

on Cancer drug resistance

Issue of 2023‒01‒15
nine papers selected by
Rana Gbyli
Yale University

STING agonism overcomes STAT3-mediated immunosuppression and adaptive resistance to PARP inhibition in ovarian cancer.
The Adaptability of Chromosomal Instability in Cancer Therapy and Resistance.
KDM6A loss triggers an epigenetic switch that disrupts urothelial differentiation and drives cell proliferation in bladder cancer.
Battles against aberrant KEAP1-NRF2 signaling in lung cancer: intertwined metabolic and immune networks.
p53 Family in Resistance to Targeted Therapy of Melanoma.
Basal-like mammary carcinomas stimulate cancer stem cell properties through AXL-signaling to induce chemotherapy resistance.
Targeting TBK1 to overcome resistance to cancer immunotherapy.
Multiplexed screens identify RAS paralogues HRAS and NRAS as suppressors of KRAS-driven lung cancer growth.
DNA dioxygenases Tet2/3 regulate gene promoter accessibility and chromatin topology in lineage-specific loci to control epithelial differentiation.

J Immunother Cancer. 2023 Jan;pii: e005627. [Epub ahead of print]11(1):

STING agonism overcomes STAT3-mediated immunosuppression and adaptive resistance to PARP inhibition in ovarian cancer.

Liya Ding, Qiwei Wang, Antons Martincuks, Michael J Kearns, Tao Jiang, Ziying Lin, Xin Cheng, Changli Qian, Shaozhen Xie, Hye-Jung Kim, Inga-Maria Launonen, Anniina Färkkilä, Thomas M Roberts, Gordon J Freeman, Joyce F Liu, Panagiotis A Konstantinopoulos, Ursula Matulonis, Hua Yu, Jean J Zhao.

  BACKGROUND: Poly (ADP-ribose) polymerase (PARP) inhibition (PARPi) has demonstrated potent therapeutic efficacy in patients with BRCA-mutant ovarian cancer. However, acquired resistance to PARPi remains a major challenge in the clinic.METHODS: PARPi-resistant ovarian cancer mouse models were generated by long-term treatment of olaparib in syngeneic Brca1-deficient ovarian tumors. Signal transducer and activator of transcription 3 (STAT3)-mediated immunosuppression was investigated in vitro by co-culture experiments and in vivo by analysis of immune cells in the tumor microenvironment (TME) of human and mouse PARPi-resistant tumors. Whole genome transcriptome analysis was performed to assess the antitumor immunomodulatory effect of STING (stimulator of interferon genes) agonists on myeloid cells in the TME of PARPi-resistant ovarian tumors. A STING agonist was used to overcome STAT3-mediated immunosuppression and acquired PARPi resistance in syngeneic and patient-derived xenografts models of ovarian cancer.
RESULTS: In this study, we uncover an adaptive resistance mechanism to PARP inhibition mediated by tumor-associated macrophages (TAMs) in the TME. Markedly increased populations of protumor macrophages are found in BRCA-deficient ovarian tumors that rendered resistance to PARPi in both murine models and patients. Mechanistically, PARP inhibition elevates the STAT3 signaling pathway in tumor cells, which in turn promotes protumor polarization of TAMs. STAT3 ablation in tumor cells mitigates polarization of protumor macrophages and increases tumor-infiltrating T cells on PARP inhibition. These findings are corroborated in patient-derived, PARPi-resistant BRCA1-mutant ovarian tumors. Importantly, STING agonists reshape the immunosuppressive TME by reprogramming myeloid cells and overcome the TME-dependent adaptive resistance to PARPi in ovarian cancer. This effect is further enhanced by addition of the programmed cell death protein-1 blockade.
CONCLUSIONS: We elucidate an adaptive immunosuppression mechanism rendering resistance to PARPi in BRCA1-mutant ovarian tumors. This is mediated by enrichment of protumor TAMs propelled by PARPi-induced STAT3 activation in tumor cells. We also provide a new strategy to reshape the immunosuppressive TME with STING agonists and overcome PARPi resistance in ovarian cancer.

Keywords:  Drug Therapy, Combination; Immunomodulation; Immunotherapy; Macrophages; Tumor Microenvironment

DOI:  https://doi.org/10.1136/jitc-2022-005627
Int J Mol Sci. 2022 Dec 23. pii: 245. [Epub ahead of print]24(1):

The Adaptability of Chromosomal Instability in Cancer Therapy and Resistance.

Vinicio Carloni, Elisa Morganti, Andrea Galli, Antonio Mazzocca.

  Variation in chromosome structure is a central source of DNA damage and DNA damage response, together representinga major hallmark of chromosomal instability. Cancer cells under selective pressure of therapy use DNA damage and DNA damage response to produce newfunctional assets as an evolutionary mechanism. Recent efforts to understand DNA damage/chromosomal instability and elucidate its role in initiation or progression of cancer have also disclosed its vulnerabilities represented by inappropriate DNA damage response, chromatin changes, andinflammation. Understanding these vulnerabilities can provide important clues for predicting treatment response and for the development of novel strategies that prevent the emergence of therapy resistant tumors.

Keywords:  DNA damage; DNA damage response; epigenetic changes; immune evasion; immunotherapy

DOI:  https://doi.org/10.3390/ijms24010245
Cancer Res. 2023 Jan 13. pii: CAN-22-1444. [Epub ahead of print]

KDM6A loss triggers an epigenetic switch that disrupts urothelial differentiation and drives cell proliferation in bladder cancer.

Hong Qiu, Vladimir Makarov, Jennifer K Bolzenius, Angela Halstead, Yvonne Parker, Allen Wang, Gopakumar V Iyer, Hannah Wise, Daniel Kim, Varna Thayaparan, Daniel J Lindner, Georges-Pascal Haber, Angela H Ting, Bing Ren, Timothy A Chan, Vivek Arora, David B Solit, Byron H Lee.

Disruption of KDM6A, a histone lysine demethylase, is one of the most common somatic alternations in bladder cancer. Insights into how KDM6A mutations impact the epigenetic landscape to promote carcinogenesis could help reveal potential new treatment approaches. Here, we demonstrated that KDM6A loss triggers an epigenetic switch that disrupts urothelial differentiation and induces a neoplastic state characterized by increased cell proliferation. In bladder cancer cells with intact KDM6A, FOXA1 interacted with KDM6A to activate genes instructing urothelial differentiation. KDM6A-deficient cells displayed simultaneous loss of FOXA1 target binding and genome-wide redistribution of the bZIP transcription factor ATF3, which in turn repressed FOXA1-target genes and activated cell cycle progression genes. Importantly, ATF3 depletion reversed the cell proliferation phenotype induced by KDM6A deficiency. These data establish that KDM6A loss engenders an epigenetic state that drives tumor growth in an ATF3-dependent manner, creating a potentially targetable molecular vulnerability.

DOI: https://doi.org/10.1158/0008-5472.CAN-22-1444
Theranostics. 2023 ;13(2): 704-723

Battles against aberrant KEAP1-NRF2 signaling in lung cancer: intertwined metabolic and immune networks.

Ke Xu, Jie Ma, Sean R R Hall, Ren-Wang Peng, Haitang Yang, Feng Yao.

  The Kelch-like ECH-associated protein 1/nuclear factor erythroid-derived 2-like 2 (KEAP1/NRF2) pathway is well recognized as a key regulator of redox homeostasis, protecting cells from oxidative stress and xenobiotics under physiological circumstances. Cancer cells often hijack this pathway during initiation and progression, with aberrant KEAP1-NRF2 activity predominantly observed in non-small cell lung cancer (NSCLC), suggesting that cell/tissue-of-origin is likely to influence the genetic selection during malignant transformation. Hyperactivation of NRF2 confers a multi-faceted role, and recently, increasing evidence shows that a close interplay between metabolic reprogramming and tumor immunity remodelling contributes to its aggressiveness, treatment resistance (radio-/chemo-/immune-therapy) and susceptibility to metastases. Here, we discuss in detail the special metabolic and immune fitness enabled by KEAP1-NRF2 aberration in NSCLC. Furthermore, we summarize the similarities and differences in the dysregulated KEAP1-NRF2 pathway between two major histo-subtypes of NSCLC, provide mechanistic insights on the poor response to immunotherapy despite their high immunogenicity, and outline evolving strategies to treat this recalcitrant cancer subset. Finally, we integrate bioinformatic analysis of publicly available datasets to illustrate the new partners/effectors in NRF2-addicted cancer cells, which may provide new insights into context-directed treatment.

Keywords:  KEAP1-NRF2 signaling; bioinformatics; metabolic reprogramming; non-small cell lung cancer; therapeutic vulnerabilities; tumor immune microenvironment

DOI:  https://doi.org/10.7150/thno.80184
Int J Mol Sci. 2022 Dec 21. pii: 65. [Epub ahead of print]24(1):

p53 Family in Resistance to Targeted Therapy of Melanoma.

Ignacija Vlašić, Anđela Horvat, Ana Tadijan, Neda Slade.

  Metastatic melanoma is one of the most aggressive tumors, with frequent mutations affecting components of the MAPK pathway, mainly protein kinase BRAF. Despite promising initial response to BRAF inhibitors, melanoma progresses due to development of resistance. In addition to frequent reactivation of MAPK or activation of PI3K/AKT signaling pathways, recently, the p53 pathway has been shown to contribute to acquired resistance to targeted MAPK inhibitor therapy. Canonical tumor suppressor p53 is inactivated in melanoma by diverse mechanisms. The TP53 gene and two other family members, TP63 and TP73, encode numerous protein isoforms that exhibit diverse functions during tumorigenesis. The p53 family isoforms can be produced by usage of alternative promoters and/or splicing on the C- and N-terminus. Various p53 family isoforms are expressed in melanoma cell lines and tumor samples, and several of them have already shown to have specific functions in melanoma, affecting proliferation, survival, metastatic potential, invasion, migration, and response to therapy. Of special interest are p53 family isoforms with increased expression and direct involvement in acquired resistance to MAPK inhibitors in melanoma cells, implying that modulating their expression or targeting their functional pathways could be a potential therapeutic strategy to overcome resistance to MAPK inhibitors in melanoma.

Keywords:  MAPK inhibitors; melanoma; p53; p53 family isoforms; p63; p73; resistance

DOI:  https://doi.org/10.3390/ijms24010065
Int J Cancer. 2023 Jan 13.

Basal-like mammary carcinomas stimulate cancer stem cell properties through AXL-signaling to induce chemotherapy resistance.

Garyfallia Pantelaiou-Prokaki, Oliver Reinhardt, Nadine S Georges, David J Agorku, Olaf Hardt, Evangelos Prokakis, Iga K Mieczkowska, Wolfgang Deppert, Florian Wegwitz, Frauke Alves.

  Basal-like breast cancer (BLBC) is the most aggressive and heterogeneous breast cancer (BC) subtype. Conventional chemotherapies represent next to surgery the most frequently employed treatment options. Unfortunately, resistant tumor phenotypes often develop, resulting in therapeutic failure. To identify the early events occurring upon the first drug application and initiating chemotherapy resistance in BLBC, we leveraged the WAP-T syngeneic mammary carcinoma mouse model and we developed a strategy combining magnetic-activated cell sorting (MACS)-based tumor cell enrichment with high-throughput transcriptome analyses. We discovered that chemotherapy-induced a massive gene expression reprogramming towards stemness acquisition to tolerate and survive the cytotoxic treatment in vitro and in vivo. Re-transplantation experiments revealed that one single cycle of cytotoxic drug combination therapy (Cyclophosphamide, Adriamycin, 5-Fluorouracil) suffices to induce resistant tumor cell phenotypes in vivo. We identified Axl and its ligand Pros1 as highly induced genes driving cancer stem cell (CSC) properties upon chemotherapy in vivo and in vitro. Furthermore, from our analysis of BLBC patient datasets, we found that AXL expression is also strongly correlated with CSC-gene signatures, a poor response to conventional therapies and worse survival outcomes in those patients. Finally, we demonstrate that AXL inhibition sensitized BLBC-cells to cytotoxic treatment in vitro. Together, our data support AXL as a promising therapeutic target to optimize the efficiency of conventional cytotoxic therapies in BLBC. This article is protected by copyright. All rights reserved.

Keywords:  AXL; Basal-like breast cancer; breast cancer stem cell; chemoresistance; syngeneic mouse model

DOI:  https://doi.org/10.1002/ijc.34429
Nature. 2023 Jan 12.

Targeting TBK1 to overcome resistance to cancer immunotherapy.

Yi Sun, Or-Yam Revach, Seth Anderson, Emily A Kessler, Clara H Wolfe, Anne Jenney, Caitlin E Mills, Emily J Robitschek, Thomas G R Davis, Sarah Kim, Amina Fu, Xiang Ma, Jia Gwee, Payal Tiwari, Peter P Du, Princy Sindurakar, Jun Tian, Arnav Mehta, Alexis M Schneider, Keren Yizhak, Moshe Sade-Feldman, Thomas LaSalle, Tatyana Sharova, Hongyan Xie, Shuming Liu, William A Michaud, Rodrigo Saad-Beretta, Kathleen B Yates, Arvin Iracheta-Vellve, Johan K E Spetz, Xingping Qin, Kristopher A Sarosiek, Gao Zhang, Jong Wook Kim, Mack Y Su, Angelina M Cicerchia, Martin Q Rasmussen, Samuel J Klempner, Dejan Juric, Sara I Pai, David M Miller, Anita Giobbie-Hurder, Jonathan H Chen, Karin Pelka, Dennie T Frederick, Susanna Stinson, Elena Ivanova, Amir R Aref, Cloud P Paweletz, David A Barbie, Debattama R Sen, David E Fisher, Ryan B Corcoran, Nir Hacohen, Peter K Sorger, Keith T Flaherty, Genevieve M Boland, Robert T Manguso, Russell W Jenkins.

Despite the success of PD-1 blockade in melanoma and other cancers, effective treatment strategies to overcome resistance to cancer immunotherapy are lacking1,2. We identified the innate immune kinase TANK-binding kinase 1 (TBK1)3 as a candidate immune evasion gene in a pooled genetic screen4. Using a suite of genetic and pharmacologic tools across multiple experimental model systems, we confirm a role for TBK1 as an immune evasion gene. Targeting TBK1 enhances response to PD-1 blockade by lowering the cytotoxicity threshold to effector cytokines (TNFα/IFNγ). TBK1 inhibition in combination with PD-1 blockade also demonstrated efficacy using patient-derived tumour models, with concordant findings in matched patient-derived organotypic tumour spheroids (PDOTS) and matched patient-derived organoids (PDOs). Tumour cells lacking TBK1 are primed to undergo RIPK- and caspase-dependent cell death in response to TNFα/IFNγ in a JAK/STAT-dependent manner. Taken together, our results demonstrate that targeting TBK1 is a novel and effective strategy to overcome resistance to cancer immunotherapy.

DOI: https://doi.org/10.1038/s41586-023-05704-6
Nat Cell Biol. 2023 Jan 12.

Multiplexed screens identify RAS paralogues HRAS and NRAS as suppressors of KRAS-driven lung cancer growth.

Rui Tang, Emily G Shuldiner, Marcus Kelly, Christopher W Murray, Jess D Hebert, Laura Andrejka, Min K Tsai, Nicholas W Hughes, Mitchell I Parker, Hongchen Cai, Yao-Cheng Li, Geoffrey M Wahl, Roland L Dunbrack, Peter K Jackson, Dmitri A Petrov, Monte M Winslow.

Oncogenic KRAS mutations occur in approximately 30% of lung adenocarcinoma. Despite several decades of effort, oncogenic KRAS-driven lung cancer remains difficult to treat, and our understanding of the regulators of RAS signalling is incomplete. Here to uncover the impact of diverse KRAS-interacting proteins on lung cancer growth, we combined multiplexed somatic CRISPR/Cas9-based genome editing in genetically engineered mouse models with tumour barcoding and high-throughput barcode sequencing. Through a series of CRISPR/Cas9 screens in autochthonous lung cancer models, we show that HRAS and NRAS are suppressors of KRASG12D-driven tumour growth in vivo and confirm these effects in oncogenic KRAS-driven human lung cancer cell lines. Mechanistically, RAS paralogues interact with oncogenic KRAS, suppress KRAS-KRAS interactions, and reduce downstream ERK signalling. Furthermore, HRAS and NRAS mutations identified in oncogenic KRAS-driven human tumours partially abolished this effect. By comparing the tumour-suppressive effects of HRAS and NRAS in oncogenic KRAS- and oncogenic BRAF-driven lung cancer models, we confirm that RAS paralogues are specific suppressors of KRAS-driven lung cancer in vivo. Our study outlines a technological avenue to uncover positive and negative regulators of oncogenic KRAS-driven cancer in a multiplexed manner in vivo and highlights the role RAS paralogue imbalance in oncogenic KRAS-driven lung cancer.

DOI: https://doi.org/10.1038/s41556-022-01049-w
Sci Adv. 2023 Jan 13. 9(2): eabo7605

DNA dioxygenases Tet2/3 regulate gene promoter accessibility and chromatin topology in lineage-specific loci to control epithelial differentiation.

Guo-Dong Chen, Iqra Fatima, Qin Xu, Elena Rozhkova, Michael Y Fessing, Andrei N Mardaryev, Andrey A Sharov, Guo-Liang Xu, Vladimir A Botchkarev.

Execution of lineage-specific differentiation programs requires tight coordination between many regulators including Ten-eleven translocation (TET) family enzymes, catalyzing 5-methylcytosine oxidation in DNA. Here, by using Keratin 14-Cre-driven ablation of Tet genes in skin epithelial cells, we demonstrate that ablation of Tet2/Tet3 results in marked alterations of hair shape and length followed by hair loss. We show that, through DNA demethylation, Tet2/Tet3 control chromatin accessibility and Dlx3 binding and promoter activity of the Krt25 and Krt28 genes regulating hair shape, as well as regulate interactions between the Krt28 gene promoter and distal enhancer. Moreover, Tet2/Tet3 also control three-dimensional chromatin topology in Keratin type I/II gene loci via DNA methylation-independent mechanisms. These data demonstrate the essential roles for Tet2/3 in establishment of lineage-specific gene expression program and control of Dlx3/Krt25/Krt28 axis in hair follicle epithelial cells and implicate modulation of DNA methylation as a novel approach for hair growth control.

DOI: https://doi.org/10.1126/sciadv.abo7605