bims-cadres Biomed News
on Cancer drug resistance
Issue of 2022‒09‒11
thirteen papers selected by
Rana Gbyli
Yale University
  1. Phase separation in epigenetics and cancer stem cells.
  2. The spindle assembly checkpoint is a therapeutic vulnerability of CDK4/6 inhibitor-resistant ER+ breast cancer with mitotic aberrations.
  3. Stochastic population dynamics of cancer stemness and adaptive response to therapies.
  4. Epigenetic Alterations under Oxidative Stress in Stem Cells.
  5. Transitioning cancer cells and the surrounding tumor environment in pancreatic cancer.
  6. Analysis of Dormancy-Associated Transcriptional Networks Reveals a Shared Quiescence Signature in Lung and Colorectal Cancer.
  7. High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer.
  8. The Regulatory Role of Lipid Metabolism in Endometrial Cancer.
  9. Q&A: John Dick on Stem Cells and Discoveries.
  10. Emerging role of ferroptosis in glioblastoma: Therapeutic opportunities and challenges.
  11. Epigenetic reprogramming in small cell lung cancer.
  12. The amino acid transporter SLC7A11-mediated crosstalk implicated in cancer therapy and the tumor microenvironment.
  13. Lineage plasticity in prostate cancer: Looking beyond intrinsic alterations.
  1. Front Oncol. 2022 ;12 922604
    Phase separation in epigenetics and cancer stem cells.
    Chanchan Xiao, Guangjie Wu, Pengfei Chen, Lijuan Gao, Guobing Chen, Hongyi Zhang.
      Accumulating evidence indicates that liquid-liquid phase separation (LLPS) is the basis of the formation of membrane-less compartments in cells. This biomolecular condensate represented by phase separation may influence epigenetics in cancer stem cells (CSCs), a small subpopulation of cancer cells responding to the initiation, maintenance, metastasis, and therapy resistance of cancer. Understanding the underlying biophysical principles and the specific characteristics of biocondensates would provide insights into the precise blocking of potential tumor targets, thereby fundamentally curbing tumor occurrence, recurrence and metastasis. In this review, we summarized the key phenomenon and experimental detection of phase separation and the possibility of regulating the stemness of CSCs through phase separation. We believe that the mechanism of phase separation in CSCs will open up new avenues for the mystery of tumor formation, and modulating phase separation will be a great strategy for CSC-targeted tumor therapy.
    Keywords:  cancer stem cells; epigenetic; liquid-liquid phase separation; phase separation; stemness
    DOI:  https://doi.org/10.3389/fonc.2022.922604
  2. Sci Adv. 2022 Sep 09. 8(36): eabq4293
    The spindle assembly checkpoint is a therapeutic vulnerability of CDK4/6 inhibitor-resistant ER+ breast cancer with mitotic aberrations.
    Isabel Soria-Bretones, Kelsie L Thu, Jennifer Silvester, Jennifer Cruickshank, Samah El Ghamrasni, Wail Ba-Alawi, Graham C Fletcher, Reza Kiarash, Mitchell J Elliott, Jordan J Chalmers, Andrea C Elia, Albert Cheng, April A N Rose, Mark R Bray, Benjamin Haibe-Kains, Tak W Mak, David W Cescon.
      Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) are standard first-line treatments for metastatic ER+ breast cancer. However, acquired resistance to CDK4/6i invariably develops, and the molecular phenotypes and exploitable vulnerabilities associated with resistance are not yet fully characterized. We developed a panel of CDK4/6i-resistant breast cancer cell lines and patient-derived organoids and demonstrate that a subset of resistant models accumulates mitotic segregation errors and micronuclei, displaying increased sensitivity to inhibitors of mitotic checkpoint regulators TTK and Aurora kinase A/B. RB1 loss, a well-recognized mechanism of CDK4/6i resistance, causes such mitotic defects and confers enhanced sensitivity to TTK inhibition. In these models, inhibition of TTK with CFI-402257 induces premature chromosome segregation, leading to excessive mitotic segregation errors, DNA damage, and cell death. These findings nominate the TTK inhibitor CFI-402257 as a therapeutic strategy for a defined subset of ER+ breast cancer patients who develop resistance to CDK4/6i.
    DOI:  https://doi.org/10.1126/sciadv.abq4293
  3. Essays Biochem. 2022 Sep 08. pii: EBC20220038. [Epub ahead of print]
    Stochastic population dynamics of cancer stemness and adaptive response to therapies.
    Paras Jain, Atchuta Srinivas Duddu, Mohit Kumar Jolly.
      Intratumoral heterogeneity can exist along multiple axes: Cancer stem cells (CSCs)/non-CSCs, drug-sensitive/drug-tolerant states, and a spectrum of epithelial-hybrid-mesenchymal phenotypes. Further, these diverse cell-states can switch reversibly among one another, thereby posing a major challenge to therapeutic efficacy. Therefore, understanding the origins of phenotypic plasticity and heterogeneity remains an active area of investigation. While genomic components (mutations, chromosomal instability) driving heterogeneity have been well-studied, recent reports highlight the role of non-genetic mechanisms in enabling both phenotypic plasticity and heterogeneity. Here, we discuss various processes underlying phenotypic plasticity such as stochastic gene expression, chromatin reprogramming, asymmetric cell division and the presence of multiple stable gene expression patterns ('attractors'). These processes can facilitate a dynamically evolving cell population such that a subpopulation of (drug-tolerant) cells can survive lethal drug exposure and recapitulate population heterogeneity on drug withdrawal, leading to relapse. These drug-tolerant cells can be both pre-existing and also induced by the drug itself through cell-state reprogramming. The dynamics of cell-state transitions both in absence and presence of the drug can be quantified through mathematical models. Such a dynamical systems approach to elucidating patterns of intratumoral heterogeneity by integrating longitudinal experimental data with mathematical models can help design effective combinatorial and/or sequential therapies for better clinical outcomes.
    Keywords:  Cancer Stem Cells; Drug resistance; Intratumoral heterogeneity; Phenotypic plasticity
    DOI:  https://doi.org/10.1042/EBC20220038
  4. Oxid Med Cell Longev. 2022 ;2022 6439097
    Epigenetic Alterations under Oxidative Stress in Stem Cells.
    Min Huang, Qiang Wu, Zhi-Hong Jiang.
      Epigenetic regulation of gene expression, including DNA methylation and histone modifications, provides finely tuned responses for cells that undergo cellular environment changes. Abundant evidences have demonstrated the detrimental role of oxidative stress in various human pathogenesis since oxidative stress results from the imbalance between reactive oxygen species (ROS) accumulation and antioxidant defense system. Stem cells can self-renew themselves and meanwhile have the potential to differentiate into many other cell types. As some studies have described the effects of oxidative stress on homeostasis and cell fate decision of stem cells, epigenetic alterations have emerged crucial for mediating the stem cell behaviours under oxidative stress. Here, we review recent findings on the oxidative effects on DNA and histone modifications in stem cells. We propose that epigenetic alterations and oxidative stress may influence each other in stem cells.
    DOI:  https://doi.org/10.1155/2022/6439097
  5. Nat Genet. 2022 Sep 05.
    Transitioning cancer cells and the surrounding tumor environment in pancreatic cancer.
      
    DOI:  https://doi.org/10.1038/s41588-022-01162-4
  6. Int J Mol Sci. 2022 Aug 30. pii: 9869. [Epub ahead of print]23(17):
    Analysis of Dormancy-Associated Transcriptional Networks Reveals a Shared Quiescence Signature in Lung and Colorectal Cancer.
    Adriano Cuccu, Federica Francescangeli, Maria Laura De Angelis, Alessandro Bruselles, Alessandro Giuliani, Ann Zeuner.
      Quiescent cancer cells (QCCs) are a common feature of solid tumors, representing a major obstacle to the long-term success of cancer therapies. We isolated QCCs ex vivo from non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) xenografts with a label-retaining strategy and compared QCCs gene expression profiles to identify a shared "quiescence signature". Principal Component Analysis (PCA) revealed a specific component neatly discriminating quiescent and replicative phenotypes in NSCLC and CRC. The discriminating component showed significant overlapping, with 688 genes in common including ZEB2, a master regulator of stem cell plasticity and epithelial-to-mesenchymal transition (EMT). Gene set enrichment analysis showed that QCCs of both NSCLC and CRC had an increased expression of factors related to stemness/self renewal, EMT, TGF-β, morphogenesis, cell adhesion and chemotaxis, whereas proliferating cells overexpressed Myc targets and factors involved in RNA metabolism. Eventually, we analyzed in depth by means of a complex network approach, both the 'morphogenesis module' and the subset of differentially expressed genes shared by NCSLC and CRC. This allowed us to recognize different gene regulation network wiring for quiescent and proliferating cells and to underpin few genes central for network integration that may represent new therapeutic vulnerabilities. Altogether, our results highlight common regulatory pathways in QCCs of lung and colorectal tumors that may be the target of future therapeutic interventions.
    Keywords:  colorectal cancer; dormancy; lung cancer; quiescence
    DOI:  https://doi.org/10.3390/ijms23179869
  7. Nat Commun. 2022 Sep 07. 13(1): 5258
    High p16 expression and heterozygous RB1 loss are biomarkers for CDK4/6 inhibitor resistance in ER+ breast cancer.
    Marta Palafox, Laia Monserrat, Meritxell Bellet, Guillermo Villacampa, Abel Gonzalez-Perez, Mafalda Oliveira, Fara Brasó-Maristany, Nusaibah Ibrahimi, Srinivasaraghavan Kannan, Leonardo Mina, Maria Teresa Herrera-Abreu, Andreu Òdena, Mònica Sánchez-Guixé, Marta Capelán, Analía Azaro, Alejandra Bruna, Olga Rodríguez, Marta Guzmán, Judit Grueso, Cristina Viaplana, Javier Hernández, Faye Su, Kui Lin, Robert B Clarke, Carlos Caldas, Joaquín Arribas, Stefan Michiels, Alicia García-Sanz, Nicholas C Turner, Aleix Prat, Paolo Nuciforo, Rodrigo Dienstmann, Chandra S Verma, Nuria Lopez-Bigas, Maurizio Scaltriti, Monica Arnedos, Cristina Saura, Violeta Serra.
      CDK4/6 inhibitors combined with endocrine therapy have demonstrated higher antitumor activity than endocrine therapy alone for the treatment of advanced estrogen receptor-positive breast cancer. Some of these tumors are de novo resistant to CDK4/6 inhibitors and others develop acquired resistance. Here, we show that p16 overexpression is associated with reduced antitumor activity of CDK4/6 inhibitors in patient-derived xenografts (n = 37) and estrogen receptor-positive breast cancer cell lines, as well as reduced response of early and advanced breast cancer patients to CDK4/6 inhibitors (n = 89). We also identified heterozygous RB1 loss as biomarker of acquired resistance and poor clinical outcome. Combination of the CDK4/6 inhibitor ribociclib with the PI3K inhibitor alpelisib showed antitumor activity in estrogen receptor-positive non-basal-like breast cancer patient-derived xenografts, independently of PIK3CA, ESR1 or RB1 mutation, also in drug de-escalation experiments or omitting endocrine therapy. Our results offer insights into predicting primary/acquired resistance to CDK4/6 inhibitors and post-progression therapeutic strategies.
    DOI:  https://doi.org/10.1038/s41467-022-32828-6
  8. J Oncol. 2022 ;2022 6458877
    The Regulatory Role of Lipid Metabolism in Endometrial Cancer.
    Shuyang Zhang, Xingyu Han.
      Endometrial cancer is the 6th most common carcinoma as well as the 2nd most common malignancy worldwide in women. It is closely related to fat content, and dyslipidemia is among the most significant metabolic changes in this cancer. Therefore, further understanding of the regulation mechanism in lipid metabolism of endometrial cancer is conducive to the development of better therapeutic strategies and methods. Here, we systematically review the signaling pathways that regulate lipid metabolism in endometrial cancer and the research progress of drugs and targeted therapies that act on lipid metabolism by retrieving relevant articles. The underlying mechanism of occurrence and development of endometrial cancer is relatively clear and comprehensively reviewed here. But following more research studies will help to illuminate more specific regulatory roles of lipid metabolism in endometrial cancer and explore new possible mechanisms, prognostic and therapeutic targets, and subsequent drugs. Our review will provide a full view for the following investigation of lipid metabolism in endometrial cancer.
    DOI:  https://doi.org/10.1155/2022/6458877
  9. Blood Cancer Discov. 2022 09 06. 3(5): 371-373
    Q&A: John Dick on Stem Cells and Discoveries.
      
    DOI:  https://doi.org/10.1158/2643-3230.BCD-22-0120
  10. Front Mol Biosci. 2022 ;9 974156
    Emerging role of ferroptosis in glioblastoma: Therapeutic opportunities and challenges.
    Shenghua Zhuo, Guiying He, Taixue Chen, Xiang Li, Yunheng Liang, Wenkai Wu, Lingxiao Weng, Jigao Feng, Zhenzhong Gao, Kun Yang.
      Glioblastoma (GBM) is the most common malignant craniocerebral tumor. The treatment of this cancer is difficult due to its high heterogeneity and immunosuppressive microenvironment. Ferroptosis is a newly found non-apoptotic regulatory cell death process that plays a vital role in a variety of brain diseases, including cerebral hemorrhage, neurodegenerative diseases, and primary or metastatic brain tumors. Recent studies have shown that targeting ferroptosis can be an effective strategy to overcome resistance to tumor therapy and immune escape mechanisms. This suggests that combining ferroptosis-based therapies with other treatments may be an effective strategy to improve the treatment of GBM. Here, we critically reviewed existing studies on the effect of ferroptosis on GBM therapies such as chemotherapy, radiotherapy, immunotherapy, and targeted therapy. In particular, this review discussed the potential of ferroptosis inducers to reverse drug resistance and enhance the sensitivity of conventional cancer therapy in combination with ferroptosis. Finally, we highlighted the therapeutic opportunities and challenges facing the clinical application of ferroptosis-based therapies in GBM. The data generated here provide new insights and directions for future research on the significance of ferroptosis-based therapies in GBM.
    Keywords:  cancer therapy; ferroptosis; glioblastoma; immunotherapy; therapy resistance
    DOI:  https://doi.org/10.3389/fmolb.2022.974156
  11. Cancer Biol Med. 2022 Aug 30. pii: j.issn.2095-3941.2022.0343. [Epub ahead of print]19(8):
    Epigenetic reprogramming in small cell lung cancer.
    Chen Jingyao, Pan Xiangyu, Na Feifei, Chen Xuelan, Chen Chong.
      
    DOI:  https://doi.org/10.20892/j.issn.2095-3941.2022.0343
  12. Biochem Pharmacol. 2022 Sep 06. pii: S0006-2952(22)00335-5. [Epub ahead of print] 115241
    The amino acid transporter SLC7A11-mediated crosstalk implicated in cancer therapy and the tumor microenvironment.
    Jiaqin He, Xiaomeng Wang, Keying Chen, Mei Zhang, Juan Wang.
      The solute carrier family 7 member 11 (SLC7A11), an amino acid transporter protein is frequently overexpressed in human malignancies. The expression and activity of SLC7A11 is finely regulated by oncogenes and tumor suppressors in tumor cells through various mechanisms and is highly specific for cystine and glutamate. Cystine is mainly transported intracellularly by SLC7A11 in the tumor microenvironment (TME) and is involved in GSH synthesis, which leads to ferroptosis resistance in tumor cells and promotes tumorigenesis and progression. The downregulation of SLC7A11 presents a unique drug discovery opportunity for ferroptosis-related diseases. Experimental work has shown that targeting SLC7A11 and tumor immunotherapy combine to trigger ferroptosis more potently. Moreover, immunotargeting of SLC7A11 increases the chemosensitivity of cancer stem cells to doxorubicin, suggesting that it may act as an adjuvant to chemotherapy. Thus, SLC7A11 could be a promising target to overcome resistance mechanisms in conventional cancer treatments. This review provides an overview of the regulatory network of SLC7A11 in the TME and progress in the development of SLC7A11 inhibitors. In addition, we summarize the cytotoxic effects of blocking SLC7A11 in cancer cells, cancer stem cells and immune cells.
    Keywords:  Anticancer; Ferroptosis; Immunotherapy; SLC7A11; SLC7A11 inhibitors
    DOI:  https://doi.org/10.1016/j.bcp.2022.115241
  13. Cancer Lett. 2022 Sep 05. pii: S0304-3835(22)00385-8. [Epub ahead of print] 215901
    Lineage plasticity in prostate cancer: Looking beyond intrinsic alterations.
    Alison M Ferguson, Mark A Rubin.
      Emergence of small cell prostate cancer is linked to the plasticity of tumour cells and avoidance of environmental pressures. This process is thought to be reversable, however to-date evidence of this has been demonstrated in small-cell prostate cancer. To study the plasticity of prostate tumours, we look to clinical cohorts of patients covering the spectra of malignancy subtypes and utilise in vitro and in vivo models of disease progression. Current models have assisted in the understanding of the extremities of this plasticity, elucidating internal mechanisms and adaptations to stressors through transition to altered cell states. By interrogating the tumour microenvironment and earlier time points, we are beginning to form a deeper understanding of the full spectra of tumour plasticity. It could be proffered that this deeper understanding will lead to better patient outcome, with earlier interventions more likely to reverse plasticity and prevent trans-differentiation to the aggressive, small cell phenotype.
    Keywords:  Differentiation; Extrinsic factors; Genomics; Lineage plasticity; Metastatic niche; Microbiome; Prostate cancer; Stemness; Therapeutic resistance; Tumour microenvironment
    DOI:  https://doi.org/10.1016/j.canlet.2022.215901
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