bims-cadres 2022-12-18 papers

bims-cadres

Biomed News

on Cancer drug resistance

Issue of 2022–12–18
twelve papers selected by
Rana Gbyli, Yale University

Multivalent state transitions shape the intratumoral composition of small cell lung carcinoma.
Cancer Stemness/Epithelial-Mesenchymal Transition Axis Influences Metastasis and Castration Resistance in Prostate Cancer: Potential Therapeutic Target.
The EMT transcription factor ZEB1 governs a fitness-promoting but vulnerable DNA replication stress response.
Clonal transcriptomics identifies mechanisms of chemoresistance and empowers rational design of combination therapies.
NSCLC Cells Resistance to PI3K/mTOR Inhibitors Is Mediated by Delta-6 Fatty Acid Desaturase (FADS2).
Effect of chromatin modifiers on the plasticity and immunogenicity of small-cell lung cancer.
Non-Small Cell Lung Cancer Targeted Therapy: Drugs and Mechanisms of Drug Resistance.
Intracellular Citrate/Acetyl-CoA Flux and Endoplasmic Reticulum Acetylation: Connectivity is the Answer.
ACSL3 and ACSL4, Distinct Roles in Ferroptosis and Cancers.
KMT2D deficiency drives lung squamous cell carcinoma and hypersensitivity to RTK-RAS inhibition.
Small ankyrin 1 (sANK1) promotes docetaxel resistance in castration-resistant prostate cancer cells by enhancing oxidative phosphorylation.
Histone lysine methyltransferase SETDB2 suppresses NRF2 to restrict tumor progression and modulates chemotherapy sensitivity in lung adenocarcinoma.

Sci Adv. 2022 Dec 14. 8(50): eabp8674

Multivalent state transitions shape the intratumoral composition of small cell lung carcinoma.

Priyanka Gopal, Aaron Petty, Kevin Rogacki, Titas Bera, Rohan Bareja, Craig D Peacock, Mohamed E Abazeed.

Studies to date have not resolved how diverse transcriptional programs contribute to the intratumoral heterogeneity of small cell lung carcinoma (SCLC), an aggressive tumor associated with a dismal prognosis. Here, we identify distinct and commutable transcriptional states that confer discrete functional attributes in individual SCLC tumors. We combine an integrative approach comprising the transcriptomes of 52,975 single cells, high-resolution measurement of cell state dynamics at the single-cell level, and functional and correlative studies using treatment naïve xenografts with associated clinical outcomes. We show that individual SCLC tumors contain distinctive proportions of stable cellular states that are governed by bidirectional cell state transitions. Using drugs that target the epigenome, we reconfigure tumor state composition in part by altering individual state transition rates. Our results reveal new insights into how single-cell transition behaviors promote cell state equilibrium in SCLC and suggest that facile plasticity underlies its resistance to therapy and lethality.

DOI: https://doi.org/10.1126/sciadv.abp8674
Int J Mol Sci. 2022 Nov 29. pii: 14917. [Epub ahead of print]23(23):

Cancer Stemness/Epithelial-Mesenchymal Transition Axis Influences Metastasis and Castration Resistance in Prostate Cancer: Potential Therapeutic Target.

Enrique A Castellón, Sebastián Indo, Héctor R Contreras.

  Prostate cancer (PCa) is a leading cause of cancer death in men, worldwide. Mortality is highly related to metastasis and hormone resistance, but the molecular underlying mechanisms are poorly understood. We have studied the presence and role of cancer stem cells (CSCs) and the Epithelial-Mesenchymal transition (EMT) in PCa, using both in vitro and in vivo models, thereby providing evidence that the stemness-mesenchymal axis seems to be a critical process related to relapse, metastasis and resistance. These are complex and related processes that involve a cooperative action of different cancer cell subpopulations, in which CSCs and mesenchymal cancer cells (MCCs) would be responsible for invading, colonizing pre-metastatic niches, initiating metastasis and an evading treatments response. Manipulating the stemness-EMT axis genes on the androgen receptor (AR) may shed some light on the effect of this axis on metastasis and castration resistance in PCa. It is suggested that the EMT gene SNAI2/Slug up regulates the stemness gene Sox2, and vice versa, inducing AR expression, promoting metastasis and castration resistance. This approach will provide new sight about the role of the stemness-mesenchymal axis in the metastasis and resistance mechanisms in PCa and their potential control, contributing to develop new therapeutic strategies for patients with metastatic and castration-resistant PCa.

Keywords:  Epithelial–Mesenchymal transition; cancer stem cell; castration resistance; metastasis; prostate cancer

DOI:  https://doi.org/10.3390/ijms232314917
Cell Rep. 2022 Dec 13. pii: S2211-1247(22)01711-9. [Epub ahead of print]41(11): 111819

The EMT transcription factor ZEB1 governs a fitness-promoting but vulnerable DNA replication stress response.

Harald Schuhwerk, Julia Kleemann, Pooja Gupta, Ruthger van Roey, Isabell Armstark, Martina Kreileder, Nora Feldker, Vignesh Ramesh, Yussuf Hajjaj, Kathrin Fuchs, Mousumi Mahapatro, Mojca Hribersek, Marco Volante, Arwin Groenewoud, Felix B Engel, Paolo Ceppi, Markus Eckstein, Arndt Hartmann, Fabian Müller, Torsten Kroll, Marc P Stemmler, Simone Brabletz, Thomas Brabletz.

  The DNA damage response (DDR) and epithelial-to-mesenchymal transition (EMT) are two crucial cellular programs in cancer biology. While the DDR orchestrates cell-cycle progression, DNA repair, and cell death, EMT promotes invasiveness, cellular plasticity, and intratumor heterogeneity. Therapeutic targeting of EMT transcription factors, such as ZEB1, remains challenging, but tumor-promoting DDR alterations elicit specific vulnerabilities. Using multi-omics, inhibitors, and high-content microscopy, we discover a chemoresistant ZEB1-high-expressing sub-population (ZEB1hi) with co-rewired cell-cycle progression and proficient DDR across tumor entities. ZEB1 stimulates accelerated S-phase entry via CDK6, inflicting endogenous DNA replication stress. However, DDR buildups involving constitutive MRE11-dependent fork resection allow homeostatic cycling and enrichment of ZEB1hi cells during transforming growth factor β (TGF-β)-induced EMT and chemotherapy. Thus, ZEB1 promotes G1/S transition to launch a progressive DDR benefitting stress tolerance, which concurrently manifests a targetable vulnerability in chemoresistant ZEB1hi cells. Our study thus highlights the translationally relevant intercept of the DDR and EMT.

Keywords:  CP: Cancer; DNA damage response; DNA replication stress; MRE11; ZEB1; cancer; cell cycle; chemoresistance; epithelial-to-mesenchymal transition; heterogeneity; plasticity

DOI:  https://doi.org/10.1016/j.celrep.2022.111819
Elife. 2022 Dec 16. pii: e80981. [Epub ahead of print]11

Clonal transcriptomics identifies mechanisms of chemoresistance and empowers rational design of combination therapies.

CRUK IMAXT Grand Challenge Team

  Tumour heterogeneity is thought to be a major barrier to successful cancer treatment due to the presence of drug resistant clonal lineages. However, identifying the characteristics of such lineages that underpin resistance to therapy has remained challenging. Here, we utilise clonal transcriptomics with WILD-seq; Wholistic Interrogation of Lineage Dynamics by sequencing, in mouse models of triple-negative breast cancer (TNBC) to understand response and resistance to therapy, including BET bromodomain inhibition and taxane-based chemotherapy. These analyses revealed oxidative stress protection by NRF2 as a major mechanism of taxane resistance and led to the discovery that our tumour models are collaterally sensitive to asparagine deprivation therapy using the clinical stage drug L-asparaginase after frontline treatment with docetaxel. In summary, clonal transcriptomics with WILD-seq identifies mechanisms of resistance to chemotherapy that are also operative in patients and pin points asparagine bioavailability as a druggable vulnerability of taxane-resistant lineages.

Keywords:  cancer biology; cancer therapy; chromosomes; gene expression; lineage tracing; mouse; single cell genomics; tumor heterogeneity

DOI:  https://doi.org/10.7554/eLife.80981
Cells. 2022 Nov 22. pii: 3719. [Epub ahead of print]11(23):

NSCLC Cells Resistance to PI3K/mTOR Inhibitors Is Mediated by Delta-6 Fatty Acid Desaturase (FADS2).

Marika Colombo, Federico Passarelli, Paola A Corsetto, Angela M Rizzo, Mirko Marabese, Giulia De Simone, Roberta Pastorelli, Massimo Broggini, Laura Brunelli, Elisa Caiola.

  Hyperactivation of the phosphatidylinositol-3-kinase (PI3K) pathway is one of the most common events in human cancers. Several efforts have been made toward the identification of selective PI3K pathway inhibitors. However, the success of these molecules has been partially limited due to unexpected toxicities, the selection of potentially responsive patients, and intrinsic resistance to treatments. Metabolic alterations are intimately linked to drug resistance; altered metabolic pathways can help cancer cells adapt to continuous drug exposure and develop resistant phenotypes. Here we report the metabolic alterations underlying the non-small cell lung cancer (NSCLC) cell lines resistant to the usual PI3K-mTOR inhibitor BEZ235. In this study, we identified that an increased unsaturation degree of lipid species is associated with increased plasma membrane fluidity in cells with the resistant phenotype and that fatty acid desaturase FADS2 mediates the acquisition of chemoresistance. Therefore, new studies focused on reversing drug resistance based on membrane lipid modifications should consider the contribution of desaturase activity.

Keywords:  BEZ235; PI3K/Akt/mTOR pathway; drug resistance; lipid metabolism; non-small-cell lung cancer

DOI:  https://doi.org/10.3390/cells11233719
Exp Mol Med. 2022 Dec 12.

Effect of chromatin modifiers on the plasticity and immunogenicity of small-cell lung cancer.

Nicole A Kirk, Kee-Beom Kim, Kwon-Sik Park.

Tumor suppressor genes (TSGs) are often involved in maintaining homeostasis. Loss of tumor suppressor functions causes cellular plasticity that drives numerous types of cancer, including small-cell lung cancer (SCLC), an aggressive type of lung cancer. SCLC is largely driven by numerous loss-of-function mutations in TSGs, often in those encoding chromatin modifiers. These mutations present a therapeutic challenge because they are not directly actionable. Alternatively, understanding the resulting molecular changes may provide insight into tumor intervention strategies. We hypothesize that despite the heterogeneous genomic landscape in SCLC, the impacts of mutations in patient tumors are related to a few important pathways causing malignancy. Specifically, alterations in chromatin modifiers result in transcriptional dysregulation, driving mutant cells toward a highly plastic state that renders them immune evasive and highly metastatic. This review will highlight studies in which imbalance of chromatin modifiers with opposing functions led to loss of immune recognition markers, effectively masking tumor cells from the immune system. This review also discusses the role of chromatin modifiers in maintaining neuroendocrine characteristics and the role of aberrant transcriptional control in promoting epithelial-to-mesenchymal transition during tumor development and progression. While these pathways are thought to be disparate, we highlight that the pathways often share molecular drivers and mediators. Understanding the relationships among frequently altered chromatin modifiers will provide valuable insights into the molecular mechanisms of SCLC development and progression and therefore may reveal preventive and therapeutic vulnerabilities of SCLC and other cancers with similar mutations.

DOI: https://doi.org/10.1038/s12276-022-00905-x
Int J Mol Sci. 2022 Dec 01. pii: 15056. [Epub ahead of print]23(23):

Non-Small Cell Lung Cancer Targeted Therapy: Drugs and Mechanisms of Drug Resistance.

Jiajia Wu, Zhenghong Lin.

  The advent of precision medicine has brought light to the treatment of non-small cell lung cancer (NSCLC), expanding the options for patients with advanced NSCLC by targeting therapy through genetic and epigenetic cues. Tumor driver genes in NSCLC patients have been uncovered one by one, including epidermal growth factor receptor (EGFR), mesenchymal lymphoma kinase (ALK), and receptor tyrosine kinase ROS proto-oncogene 1 (ROS1) mutants. Antibodies and inhibitors that target the critical gene-mediated signaling pathways that regulate tumor growth and development are anticipated to increase patient survival and quality of life. Targeted drugs continue to emerge, with as many as two dozen approved by the FDA, and chemotherapy and targeted therapy have significantly improved patient prognosis. However, resistance due to cancer drivers' genetic alterations has given rise to significant challenges in treating patients with metastatic NSCLC. Here, we summarized the main targeted therapeutic sites of NSCLC drugs and discussed their resistance mechanisms, aiming to provide new ideas for follow-up research and clues for the improvement of targeted drugs.

Keywords:  EGFR; NSCLC; drug resistance; molecular mechanisms; targeted therapy

DOI:  https://doi.org/10.3390/ijms232315056
Mol Metab. 2022 Dec 10. pii: S2212-8778(22)00222-8. [Epub ahead of print] 101653

Intracellular Citrate/Acetyl-CoA Flux and Endoplasmic Reticulum Acetylation: Connectivity is the Answer.

Gonzalo Fernandez-Fuente, Michael J Rigby, Luigi Puglielli.

   BACKGROUND: Key cellular metabolites reflecting the immediate activity of metabolic enzymes as well as the functional metabolic state of intracellular organelles can act as powerful signal regulators to ensure the activation of homeostatic responses. The citrate/acetyl-CoA pathway, initially recognized for its role in intermediate metabolism, has emerged as a fundamental branch of this nutrient-sensing homeostatic response. Emerging studies indicate that fluctuations in acetyl-CoA availability within different cellular organelles and compartments provides substrate-level regulation of many biological functions. A fundamental aspect of these regulatory functions involves Nε-lysine acetylation.
SCOPE OF REVIEW: Here, we will examine the emerging regulatory functions of the citrate/acetyl-CoA pathway and the specific role of the endoplasmic reticulum (ER) acetylation machinery in the maintenance of intracellular crosstalk and homeostasis. These functions will be analyzed in the context of associated human diseases and specific mouse models of dysfunctional ER acetylation and citrate/acetyl-CoA flux. A primary objective of this review is to highlight the complex yet integrated response of compartment- and organelle-specific Nε-lysine acetylation to the intracellular availability and flux of acetyl-CoA, linking this important post-translational modification to cellular metabolism.
MAJOR CONCLUSIONS: The ER acetylation machinery regulates the proteostatic functions of the organelle as well as metabolic crosstalk between different intracellular organelles and compartments. This crosstalk enables the cell to impart adaptive responses within the ER and the secretory pathway. However, it also enables the ER to impart adaptive responses within different cellular organelles and compartments. Defects in the homeostatic balance of acetyl-CoA flux and ER acetylation reflect different but converging disease states in humans as well as converging phenotypes in relevant mouse models. In conclusion, citrate and acetyl-CoA should not only be seen as metabolic substrates of intermediate metabolism but also as signaling molecules that direct functional adaptation of the cell to both intracellular and extracellular messages. Future discoveries in CoA biology and acetylation are likely to yield novel therapeutic approaches.

Keywords:  Acetyl-CoA; Acetylation; Citrate; CoA; Endoplasmic Reticulum

DOI:  https://doi.org/10.1016/j.molmet.2022.101653
Cancers (Basel). 2022 Nov 29. pii: 5896. [Epub ahead of print]14(23):

ACSL3 and ACSL4, Distinct Roles in Ferroptosis and Cancers.

Yufei Yang, Ting Zhu, Xu Wang, Fen Xiong, Zhangmin Hu, Xuehan Qiao, Xiao Yuan, Deqiang Wang.

  The long-chain fatty acyl CoA synthetase (ACSLs) family of enzymes contributes significantly to lipid metabolism and produces acyl-coenzyme A by catalyzing fatty acid oxidation. The dysregulation of ACSL3 and ACSL4, which belong to the five isoforms of ACSLs, plays a key role in cancer initiation, development, metastasis, and tumor immunity and may provide several possible therapeutic strategies. Moreover, ACSL3 and ACSL4 are crucial for ferroptosis, a non-apoptotic cell death triggered by the accumulation of membrane lipid peroxides due to iron overload. Here, we present a summary of the current knowledge on ACSL3 and ACSL4 and their functions in various cancers. Research on the molecular mechanisms involved in the regulation of ferroptosis is critical to developing targeted therapies for cancer.

Keywords:  ACSL3; ACSL4; cancer; ferroptosis

DOI:  https://doi.org/10.3390/cancers14235896
Cancer Cell. 2022 Dec 07. pii: S1535-6108(22)00562-1. [Epub ahead of print]

KMT2D deficiency drives lung squamous cell carcinoma and hypersensitivity to RTK-RAS inhibition.

Yuanwang Pan, Han Han, Hai Hu, Hua Wang, Yueqiang Song, Yuan Hao, Xinyuan Tong, Ayushi S Patel, Selim Misirlioglu, Sittinon Tang, Hsin-Yi Huang, Ke Geng, Ting Chen, Angeliki Karatza, Fiona Sherman, Kristen E Labbe, Fan Yang, Alison Chafitz, Chengwei Peng, Chenchen Guo, Andre L Moreira, Vamsidhar Velcheti, Sally C M Lau, Pengfei Sui, Haiquan Chen, J Alan Diehl, Anil K Rustgi, Adam J Bass, John T Poirier, Xiaoyang Zhang, Hongbin Ji, Hua Zhang, Kwok-Kin Wong.

  Lung squamous cell carcinoma (LUSC) represents a major subtype of lung cancer with limited treatment options. KMT2D is one of the most frequently mutated genes in LUSC (>20%), and yet its role in LUSC oncogenesis remains unknown. Here, we identify KMT2D as a key regulator of LUSC tumorigenesis wherein Kmt2d deletion transforms lung basal cell organoids to LUSC. Kmt2d loss increases activation of receptor tyrosine kinases (RTKs), EGFR and ERBB2, partly through reprogramming the chromatin landscape to repress the expression of protein tyrosine phosphatases. These events provoke a robust elevation in the oncogenic RTK-RAS signaling. Combining SHP2 inhibitor SHP099 and pan-ERBB inhibitor afatinib inhibits lung tumor growth in Kmt2d-deficient LUSC murine models and in patient-derived xenografts (PDXs) harboring KMT2D mutations. Our study identifies KMT2D as a pivotal epigenetic modulator for LUSC oncogenesis and suggests that KMT2D loss renders LUSC therapeutically vulnerable to RTK-RAS inhibition.

Keywords:  EGFR; ERBB2; KMT2D; SHP2; lung squamous cell carcinoma; organoids

DOI:  https://doi.org/10.1016/j.ccell.2022.11.015
FEBS Open Bio. 2022 Dec 12.

Small ankyrin 1 (sANK1) promotes docetaxel resistance in castration-resistant prostate cancer cells by enhancing oxidative phosphorylation.

Yang Yang, Haixiang Qin, Meng Ding, Changwei Ji, Wei Chen, Wenli Diao, Haoli Yin, Mengxia Chen, Weidong Gan, Hongqian Guo.

  Docetaxel (DTX) plays an important role in treating advanced prostate cancer (PCa). However, nearly all patients receiving DTX therapy ultimately progress to DTX resistance. How to address DTX resistance in PCa remains a key challenge for all urologists. Small ankyrin 1 (sAnk1) is an integral membrane protein in the endoplasmic reticulum. In the present study, we identified that sAnk1 is upregulated in PCa tissues and is positively associated with DTX therapy resistance in PCa. Further investigation demonstrated that overexpression of sAnk1 can significantly increase the DTX-resistant ability of PCa cells in vitro and in vivo. In addition, overexpression of sAnk1 could enhance oxidative phosphorylation (OXPHOS) levels in PCa cells, which was consistent with the higher OXPHOS levels observed in DTX-resistant PCa cells as compared to DTX-sensitive PCa cells. sAnk1 was also found to interact with polypyrimidine-tract binding protein (PTBP1), an alternative splicing factor, and suppressed PTBP1-mediated alternative splicing of the pyruvate kinase gene (PKM). Thus, overexpression of sAnk1decreased the ratio of PKM2/PKM1, enhanced the OXPHOS level, and ultimately promoted the resistance of PCa cells to DTX. In summary, our data suggest that sAnk1 enhances DTX resistance in PCa cells.

Keywords:  OXPHOS; PTBP1; docetaxel resistance; prostate cancer; sANK1

DOI:  https://doi.org/10.1002/2211-5463.13535
Cancer Med. 2022 Dec 12.

Histone lysine methyltransferase SETDB2 suppresses NRF2 to restrict tumor progression and modulates chemotherapy sensitivity in lung adenocarcinoma.

Guangda Yuan, Bowen Hu, Jun Ma, Chuanyu Zhang, Hongya Xie, Tengteng Wei, Yong Yang, Bin Ni.

   OBJECTIVE: Aberrant epigenetic remodeling represents a molecular hallmark in lung adenocarcinoma (LUAD). We aim to investigate the biological roles of SETDB2 and its underlying associations with oxidative stress, providing therapeutic targets for individualized treatment of LUAD.
METHODS: Differential analysis was conducted via Limma package, and Kaplan-Meier analysis was performed with survival package. CCK-8, cell proliferation assay, transwell assay, and in vivo assays were conducted to assess the function of SETDB2. Western blot assay, RT-qPCR, and immunohistochemistry (IHC) were conducted to assess the expression levels of SETDB2/NRF2. Chromatin immunoprecipitation (ChIP) assay and ChIP-qPCR were conducted to assess the epigenetic roles of SETDB2.
RESULTS: We found that SETDB2 expression is decreased in tumor samples versus normal tissues in TCGA-LUAD cohort, LUAD-EAS cohort, GSE72094 dataset, and independent Soochow-LUAD dataset. Patients with low SETDB2 levels had a worse prognosis relative to those with high SETDB2. SETDB2 inhibition could significantly promote cell growth, migration ability, and stemness maintenance. Gene set enrichment analysis (GSEA) suggested that SETDB2 correlated with oxidative stress crosstalk and regulated NRF2 mRNA levels. ChIP assay suggested that SETDB2 mainly recruited the H3K9me3 enrichment at the NRF2 promoter region to suppress the mRNA levels of NRF2. Downregulated SETDB2 could activate NRF2 transcription and expression, thereby promoting its downstream targets, like NQO1, FTH1, and ME1. Functional experiments demonstrated that low SETDB2 allowed NRF2 to drive malignant processes of LUAD. SETDB2 overexpression attenuated the ability of NRF2 signaling to neutralize cellular reactive oxygen species (ROS) levels, leading to enhanced cell apoptosis. Overexpressed SETDB2 could inhibit tumor progression in vivo and further render LUAD cells sensitive to chemotherapy.
CONCLUSIONS: In conclusion, these findings uncovered the suppressive role of SETDB2 in LUAD. SETDB2 negatively regulates NRF2 signaling to modulate tumor progression, which creates a therapeutic vulnerability in LUAD.

Keywords:  LUAD; NRF2; SETDB2; chemotherapy; epigenetic regulation

DOI:  https://doi.org/10.1002/cam4.5451