bims-cadres Biomed News
on Cancer drug resistance
Issue of 2022–11–13
nine papers selected by
Rana Gbyli, Yale University
  1. Epigenetic Disruption Enables Cancer Cells to Resist Environmental Stress.
  2. Chronic restraint stress promotes the tumorigenic potential of oral squamous cell carcinoma cells by reprogramming fatty acid metabolism via CXCL3 mediated Wnt/β-catenin pathway.
  3. Extrachromosomal DNA (ecDNA): an origin of tumor heterogeneity, genomic remodeling, and drug resistance.
  4. Targeting the MITF/APAF-1 axis as salvage therapy for MAPK inhibitors in resistant melanoma.
  5. Lipid metabolism reprogramming in colorectal cancer.
  6. Dysregulated lipid synthesis by oncogenic IDH1 mutation is a targetable synthetic lethal vulnerability.
  7. Cellular plasticity and immune microenvironment of malignant pleural effusion are associated with EGFR-TKI resistance in non-small-cell lung carcinoma.
  8. Cancer-selective metabolic vulnerabilities in MYC-amplified medulloblastoma.
  9. Stearoyl CoA Desaturase-1 Silencing in Glioblastoma Cells: Phospholipid Remodeling and Cytotoxicity Enhanced upon Autophagy Inhibition.
  1. Cancer Discov. 2022 Nov 11. OF1
    Epigenetic Disruption Enables Cancer Cells to Resist Environmental Stress.
      Loss of epigenetic regulators enables cancer cells to survive stress through phenotypic inertia.
    DOI:  https://doi.org/10.1158/2159-8290.CD-RW2022-200
  2. Exp Neurol. 2022 Nov 04. pii: S0014-4886(22)00293-X. [Epub ahead of print] 114268
    Chronic restraint stress promotes the tumorigenic potential of oral squamous cell carcinoma cells by reprogramming fatty acid metabolism via CXCL3 mediated Wnt/β-catenin pathway.
    Fangzhi Lou, Huiqing Long, Shihong Luo, Yiyun Liu, Juncai Pu, Haiyang Wang, Ping Ji, Xin Jin.
      Chronic stress promotes tumor progression and may harm homeostasis of energy metabolism by disrupting key metabolic processes. Recently, emerging evidence that chemokines CXCL3 as a novel adipokine plays a new role in lipid metabolism and various human malignancies. However, the role and mechanism of the CXCL3 in oral squamous cell carcinoma (OSCC) progression and reprogramming lipid metabolism induced by chronic restraint stress is unclear. The analysis of transcriptome sequencing, LC-MS, GC-MS, CCK8, cell apoptosis assays, cell cycle analysis, qRT-PCR, ELISA, western blotting, immunofluorescence, immunohistochemistry, RNA interference and lentivirus transfection and a xenograft tumor growth and chronic restraint stress model were used to investigate the role of CXCL3 in the regulation of lipid metabolism and OSCC and explore the underlying molecular mechanisms. We showed that CXCL3 plays a critical role in in fatty acid de novo synthesis and tumor growth induced by chronic restraint stress. We demonstrated that chronic restraint stress promoted lipid accumulation, OSCC growth and metastasis in a mouse xenograft model. CXCL3 knockdown and FH535, an inhibitor of Wnt/β-catenin pathway, could attenuate fatty acid de novo synthesis, cell proliferation and epithelial-mesenchymal transition induced by chronic restraint stress in OSCC cells. Our findings demonstrate that chronic restraint stress promotes the proliferation and metastasis of OSCC by reprogramming fatty acid metabolism via CXCL3 mediated Wnt/β-catenin pathway. Our study provides novel insights to help understand the underlying mechanisms of CXCL3 in OSCC progression induced by chronic restraint stress.
    Keywords:  CXCL3; Chronic restraint stress; Epithelial-mesenchymal transition; Lipid metabolism; Oral squamous cell carcinoma
    DOI:  https://doi.org/10.1016/j.expneurol.2022.114268
  3. Biochem Soc Trans. 2022 Nov 10. pii: BST20221045. [Epub ahead of print]
    Extrachromosomal DNA (ecDNA): an origin of tumor heterogeneity, genomic remodeling, and drug resistance.
    Lauren T Pecorino, Roel G W Verhaak, Anton Henssen, Paul S Mischel.
      The genome of cancer cells contains circular extrachromosomal DNA (ecDNA) elements not found in normal cells. Analysis of clinical samples reveal they are common in most cancers and their presence indicates poor prognosis. They often contain enhancers and driver oncogenes that are highly expressed. The circular ecDNA topology leads to an open chromatin conformation and generates new gene regulatory interactions, including with distal enhancers. The absence of centromeres leads to random distribution of ecDNAs during cell division and genes encoded on them are transmitted in a non-mendelian manner. ecDNA can integrate into and exit from chromosomal DNA. The numbers of specific ecDNAs can change in response to treatment. This dynamic ability to remodel the cancer genome challenges long-standing fundamentals, providing new insights into tumor heterogeneity, cancer genome remodeling, and drug resistance.
    Keywords:  cancer genome; drug resistance; extrachromosomal DNA; genomic remodelling; oncogenes; tumor heterogeneity
    DOI:  https://doi.org/10.1042/BST20221045
  4. Cell Rep. 2022 Nov 08. pii: S2211-1247(22)01466-8. [Epub ahead of print]41(6): 111601
    Targeting the MITF/APAF-1 axis as salvage therapy for MAPK inhibitors in resistant melanoma.
    Pietro Carotenuto, Alessia Romano, Anna Barbato, Paola Quadrano, Simona Brillante, Mariagrazia Volpe, Luigi Ferrante, Roberta Tammaro, Manuela Morleo, Rossella De Cegli, Antonella Iuliano, Marialuisa Testa, Fabrizio Andreone, Gennaro Ciliberto, Eduardo Clery, Giancarlo Troncone, Giuseppe Palma, Claudio Arra, Antonio Barbieri, Mariaelena Capone, Gabriele Madonna, Paolo A Ascierto, Luisa Lanfrancone, Alessia Indrieri, Brunella Franco.
      Melanoma is a deadly form of cancer characterized by remarkable therapy resistance. Analyzing the transcriptome of MAPK inhibitor sensitive- and resistant-melanoma, we discovered that APAF-1 is negatively regulated by MITF in resistant tumors. This study identifies the MITF/APAF-1 axis as a molecular driver of MAPK inhibitor resistance. A drug-repositioning screen identified quinacrine and methylbenzethonium as potent activators of apoptosis in a context that mimics drug resistance mediated by APAF-1 inactivation. The compounds showed anti-tumor activity in in vitro and in vivo models, linked to suppression of MITF function. Both drugs profoundly sensitize melanoma cells to MAPK inhibitors, regulating key signaling networks in melanoma, including the MITF/APAF-1 axis. Significant activity of the two compounds in inhibiting specific epigenetic modulators of MITF/APAF-1 expression, such as histone deacetylases, was observed. In summary, we demonstrate that targeting the MITF/APAF-1 axis may overcome resistance and could be exploited as a potential therapeutic approach to treat resistant melanoma.
    Keywords:  CP: Cancer; melanoma drug resistance, MAPK inhibitors, drug repositioning, MITF, APAF-1, epigenetic drugs, apoptosome, drug repositioning, apoptosome-independent cell death
    DOI:  https://doi.org/10.1016/j.celrep.2022.111601
  5. J Cell Biochem. 2022 Nov 05.
    Lipid metabolism reprogramming in colorectal cancer.
    Dan Chen, Xuebing Zhou, PengYu Yan, Chunyu Yang, Yuan Li, Longzhe Han, Xiangshan Ren.
      The hallmark feature of metabolic reprogramming is now considered to be widespread in many malignancies, including colorectal cancer (CRC). Of the gastrointestinal tumors, CRC is one of the most common with a high metastasis rate and long insidious period. The incidence and mortality of CRC has increased in recent years. Metabolic reprogramming also has a significant role in the development and progression of CRC, especially lipid metabolic reprogramming. Many studies have reported that lipid metabolism reprogramming is similar to the Warburg effect with typical features affecting tumor biology including proliferation, migration, local invasion, apoptosis, and other biological behaviors of cancer cells. Therefore, studying the role of lipid metabolism in the occurrence and development of CRC will increase our understanding of its pathogenesis, invasion, metastasis, and other processes and provide new directions for the treatment of CRC. In this paper, we mainly describe the molecular mechanism of lipid metabolism reprogramming and its important role in the occurrence and development of CRC. In addition, to provide reference for subsequent research and clinical diagnosis and treatment we also review the treatments of CRC that target lipid metabolism.
    Keywords:  colorectal cancer; lipid metabolism reprogramming; metastasis; proliferation; targeted drugs
    DOI:  https://doi.org/10.1002/jcb.30347
  6. Cancer Discov. 2022 Nov 10. pii: CD-21-0218. [Epub ahead of print]
    Dysregulated lipid synthesis by oncogenic IDH1 mutation is a targetable synthetic lethal vulnerability.
    Daniel Thomas, Manhong Wu, Yusuke Nakauchi, Ming Zheng, Chloe Al Thompson-Peach, Kelly Lim, Niklas Landberg, Thomas Köhnke, Nirmal Robinson, Satinder Kaur, Monika Kutyna, Melissa Stafford, Devendra Hiwase, Andreas Reinisch, Gary Peltz, Ravindra Majeti.
      Isocitrate dehydrogenase 1 and 2 (IDH) are mutated in multiple cancers and drive production of (R)-2-hydroxyglutarate (2HG). We identified a lipid synthesis enzyme (acetyl CoA carboxylase 1, ACC1) as a synthetic lethal target in mutant IDH1 (mIDH1), but not mIDH2, cancers. Here, we analyzed the metabolome of primary acute myeloid leukemia (AML) blasts and identified a mIDH1-specific reduction in fatty acids. mIDH1 also induced a switch to beta-oxidation indicating reprogramming of metabolism towards a reliance on fatty acids. Compared to mIDH2, mIDH1 AML displayed depletion of NADPH with defective reductive carboxylation that was not rescued by the mIDH1-specific inhibitor ivosidenib. In xenograft models, a lipid-free diet markedly slowed the growth of mIDH1 AML, but not healthy CD34+ HSPCs or mIDH2 AML. Genetic and pharmacologic targeting of ACC1 resulted in growth inhibition of mIDH1 cancers, not reversible by ivosidenib. Critically, pharmacologic targeting of ACC1 improved sensitivity of mIDH1 AML to venetoclax.
    DOI:  https://doi.org/10.1158/2159-8290.CD-21-0218
  7. iScience. 2022 Nov 18. 25(11): 105358
    Cellular plasticity and immune microenvironment of malignant pleural effusion are associated with EGFR-TKI resistance in non-small-cell lung carcinoma.
    Hyoung-Oh Jeong, Hayoon Lee, Hyemin Kim, Jinho Jang, Seunghoon Kim, Taejoo Hwang, David Whee-Young Choi, Hong Sook Kim, Naeun Lee, Yoo Mi Lee, Sehhoon Park, Hyun Ae Jung, Jong-Mu Sun, Jin Seok Ahn, Myung-Ju Ahn, Keunchil Park, Semin Lee, Se-Hoon Lee.
      Malignant pleural effusion (MPE) is a complication of lung cancer that can be used as an alternative method for tissue sampling because it is generally simple and minimally invasive. Our study evaluated the diagnostic potential of non-small-cell lung carcinoma (NSCLC)-associated MPE in terms of understanding tumor heterogeneity and identifying response factors for EGFR tyrosine kinase inhibitor (TKI) therapy. We performed a single-cell RNA sequencing analysis of 31,743 cells isolated from the MPEs of 9 patients with NSCLC (5 resistant and 4 sensitive to EGFR TKI) with EGFR mutations. Interestingly, lung epithelial precursor-like cells with upregulated GNB2L1 and CAV1 expression were enriched in the EGFR TKI-resistant group. Moreover, GZMK upregulated transitional effector T cells, and plasmacytoid dendritic cells were significantly enriched in the EGFR TKI-resistant patients. Our results suggest that cellular plasticity and immunosuppressive microenvironment in MPEs are potentially associated with the TKI response of patients with EGFR-mutated NSCLC.
    Keywords:  Cancer; immunology; omics; transcriptomics
    DOI:  https://doi.org/10.1016/j.isci.2022.105358
  8. Cancer Cell. 2022 Oct 31. pii: S1535-6108(22)00500-1. [Epub ahead of print]
    Cancer-selective metabolic vulnerabilities in MYC-amplified medulloblastoma.
    William D Gwynne, Yujin Suk, Stefan Custers, Nicholas Mikolajewicz, Jeremy K Chan, Zsolt Zador, Shawn C Chafe, Kui Zhai, Laura Escudero, Cunjie Zhang, Olga Zaslaver, Chirayu Chokshi, Muhammad Vaseem Shaikh, David Bakhshinyan, Ian Burns, Iqra Chaudhry, Omri Nachmani, Daniel Mobilio, William T Maich, Patricia Mero, Kevin R Brown, Andrew T Quaile, Chitra Venugopal, Jason Moffat, J Rafael Montenegro-Burke, Sheila K Singh.
      MYC-driven medulloblastoma (MB) is an aggressive pediatric brain tumor characterized by therapy resistance and disease recurrence. Here, we integrated data from unbiased genetic screening and metabolomic profiling to identify multiple cancer-selective metabolic vulnerabilities in MYC-driven MB tumor cells, which are amenable to therapeutic targeting. Among these targets, dihydroorotate dehydrogenase (DHODH), an enzyme that catalyzes de novo pyrimidine biosynthesis, emerged as a favorable candidate for therapeutic targeting. Mechanistically, DHODH inhibition acts on target, leading to uridine metabolite scarcity and hyperlipidemia, accompanied by reduced protein O-GlcNAcylation and c-Myc degradation. Pyrimidine starvation evokes a metabolic stress response that leads to cell-cycle arrest and apoptosis. We further show that an orally available small-molecule DHODH inhibitor demonstrates potent mono-therapeutic efficacy against patient-derived MB xenografts in vivo. The reprogramming of pyrimidine metabolism in MYC-driven medulloblastoma represents an unappreciated therapeutic strategy and a potential new class of treatments with stronger cancer selectivity and fewer neurotoxic sequelae.
    Keywords:  DHODH; brain tumor initiating cells; c-Myc; medulloblastoma; metabolic reprogramming; pyrimidine metabolism
    DOI:  https://doi.org/10.1016/j.ccell.2022.10.009
  9. Int J Mol Sci. 2022 Oct 27. pii: 13014. [Epub ahead of print]23(21):
    Stearoyl CoA Desaturase-1 Silencing in Glioblastoma Cells: Phospholipid Remodeling and Cytotoxicity Enhanced upon Autophagy Inhibition.
    Catarina M Morais, Ana M Cardoso, Ana Rita D Araújo, Ana Reis, Pedro Domingues, Maria Rosário M Domingues, Maria C Pedroso de Lima, Amália S Jurado.
      Modulation of lipid metabolism is a well-established cancer hallmark, and SCD1 has been recognized as a key enzyme in promoting cancer cell growth, including in glioblastoma (GBM), the deadliest brain tumor and a paradigm of cancer resistance. The central goal of this work was to identify, by MS, the phospholipidome alterations resulting from the silencing of SCD1 in human GBM cells, in order to implement an innovative therapy to fight GBM cell resistance. With this purpose, RNAi technology was employed, and low serum-containing medium was used to mimic nutrient deficiency conditions, at which SCD1 is overexpressed. Besides the expected increase in the saturated to unsaturated fatty acid ratio in SCD1 silenced-GBM cells, a striking increase in polyunsaturated chains, particularly in phosphatidylethanolamine and cardiolipin species, was noticed and tentatively correlated with an increase in autophagy (evidenced by the increase in LC3BII/I ratio). The contribution of autophagy to mitigate the impact of SCD1 silencing on GBM cell viability and growth, whose modest inhibition could be correlated with the maintenance of energetically associated mitochondria, was evidenced by using autophagy inhibitors. In conclusion, SCD1 silencing could constitute an important tool to halt GBM resistance to the available treatments, especially when coupled with a mitochondria disrupter chemotherapeutic.
    Keywords:  RNA interference technology; autophagy inhibition; cell viability and proliferation; fatty acid and phospholipid composition; glioblastoma; mass spectrometry; mitochondria respiratory activity; stearoyl CoA-desaturase 1 (SCD1)
    DOI:  https://doi.org/10.3390/ijms232113014
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