bims-cadres Biomed News
on Cancer drug resistance
Issue of 2023‒01‒01
eight papers selected by
Rana Gbyli
Yale University
  1. Cancer Plasticity: Investigating the causes for this agility.
  2. A ubiquitination cascade regulating the integrated stress response and survival in carcinomas.
  3. DYRK2 downregulation in colorectal cancer leads to epithelial-mesenchymal transition induction and chemoresistance.
  4. The connection between innervation and metabolic rearrangements in pancreatic cancer through serine.
  5. The lipid flippase SLC47A1 blocks metabolic vulnerability to ferroptosis.
  6. DUSP6 mediates resistance to JAK2 inhibition and drives leukemic progression.
  7. The landscape of therapeutic vulnerabilities in EGFR inhibitor osimertinib drug tolerant persister cells.
  8. Autocrine EGF and TGF-α promote primary and acquired resistance to ALK/c-Met kinase inhibitors in non-small-cell lung cancer.
  1. Semin Cancer Biol. 2022 Dec 27. pii: S1044-579X(22)00259-0. [Epub ahead of print]
    Cancer Plasticity: Investigating the causes for this agility.
    Shubhraneel Saha, Nikita Pradhan, B Neha, Ravikiran Mahadevappa, Shilpi Minocha, Saran Kumar.
      Cancer is not a hard-wired phenomenon but an evolutionary disease. From the onset of carcinogenesis, cancer cells continuously adapt and evolve to satiate their ever-growing proliferation demands. This results in the formation of multiple subtypes of cancer cells with different phenotypes, cellular compositions, and consequently displaying varying degrees of tumorigenic identity and function. This phenomenon is referred to as cancer plasticity, during which the cancer cells exist in a plethora of cellular states having distinct phenotypes. With the advent of modern technologies equipped with enhanced resolution and depth, for example, single-cell RNA-sequencing and advanced computational tools, unbiased cancer profiling at a single-cell resolution are leading the way in understanding cancer cell rewiring both spatially and temporally. In this review, the processes and mechanisms that give rise to cancer plasticity include both intrinsic genetic factors such as epigenetic changes, differential expression due to changes in DNA, RNA, or protein content within the cancer cell, as well as extrinsic environmental factors such as tissue perfusion, extracellular milieu are detailed and their influence on key cancer plasticity hallmarks such as epithelial-mesenchymal transition (EMT) and cancer cell stemness (CSCs) are discussed. Due to therapy evasion and drug resistance, tumor heterogeneity caused by cancer plasticity has major therapeutic ramifications. Hence, it is crucial to comprehend all the cellular and molecular mechanisms that control cellular plasticity. How this process evades therapy, and the therapeutic avenue of targeting cancer plasticity must be diligently investigated.
    Keywords:  Cancer Stem Cells; Cancer heterogeneity; Cancer plasticity; Cancer therapy; Epithelial-Mesenchymal Transition; Therapy resistance; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.semcancer.2022.12.005
  2. Cancer Discov. 2022 Dec 28. pii: CD-22-1230. [Epub ahead of print]
    A ubiquitination cascade regulating the integrated stress response and survival in carcinomas.
    Lisa D Cervia, Tsukasa Shibue, Ashir A Borah, Benjamin Gaeta, Linh He, Lisa Leung, Naomi Li, Sydney M Moyer, Brian H Shim, Nancy Dumont, Alfredo Gonzalez, Nolan R Bick, Mariya Kazachkova, Joshua M Dempster, John Michael Krill-Burger, Federica Piccioni, Namrata D Udeshi, Meagan E Olive, Steven A Carr, David E Root, James M McFarland, Francisca Vazquez, William C Hahn.
      Systematic identification of signaling pathways required for the fitness of cancer cells will facilitate the development of new cancer therapies. We used gene essentiality measurements in 1,086 cancer cell lines to identify selective co-essentiality modules and found that a ubiquitin ligase complex composed of UBA6, BIRC6, KCMF1 and UBR4, which is required for the survival of a subset of epithelial tumors that exhibit a high degree of aneuploidy. Suppressing BIRC6 in cell lines that are dependent on this complex led to a substantial reduction in cell fitness in vitro and potent tumor regression in vivo. Mechanistically, BIRC6 suppression resulted in selective activation of the integrated stress response (ISR) by stabilization of the heme-regulated inhibitor (HRI), a direct ubiquitination target of the UBA6/BIRC6/KCMF1/UBR4 complex. These observations uncover a novel ubiquitination cascade that regulates ISR and highlight the potential of ISR activation as a new therapeutic strategy.
    DOI:  https://doi.org/10.1158/2159-8290.CD-22-1230
  3. Sci Rep. 2022 Dec 28. 12(1): 22496
    DYRK2 downregulation in colorectal cancer leads to epithelial-mesenchymal transition induction and chemoresistance.
    Chunrong Wu, Guiyin Sun, Fan Wang, Jiangyan Chen, Fangbiao Zhan, Xiaojuan Lian, Jie Wang, Fanbin Weng, Bo Li, Weijun Tang, Jin Quan, Debing Xiang.
      Colorectal cancer (CRC) is among the most prominent causes of cancer-associated mortality in the world, with chemoresistance representing one of the leading causes of treatment failure. However, the mechanisms governing such chemoresistance remain incompletely understood. In this study, the role of DYRK2 as a mediator of CRC cell drug resistance and the associated molecular mechanisms were assessed by evaluating human tumor tissue samples, CRC cell lines, and animal model systems. Initial analyses of The Cancer Genome Atlas database and clinical tissue microarrays revealed significant DYRK2 downregulation in CRC in a manner correlated with poor prognosis. We further generated LoVo CRC cells that were resistant to the chemotherapeutic drug 5-FU, and found that such chemoresistance was associated with the downregulation of DYRK2 and a more aggressive mesenchymal phenotype. When DYRK2 was overexpressed in these cells, their proliferative, migratory, and invasive activities were reduced and they were more prone to apoptotic death. DYRK2 overexpression was also associated with enhanced chemosensitivity and the inhibition of epithelial-mesenchymal transition (EMT) induction in these LoVo 5-FUR cells. Co-immunoprecipitation assays revealed that DYRK2 bound to Twist and promoted its proteasomal degradation. In vivo studies further confirmed that the overexpression of DYRK2 inhibited human CRC xenograft tumor growth with concomitant Twist downregulation. Overall, these results thus highlight DYRK2 as a promising therapeutic target in CRC worthy of further investigation.
    DOI:  https://doi.org/10.1038/s41598-022-25053-0
  4. Front Oncol. 2022 ;12 992927
    The connection between innervation and metabolic rearrangements in pancreatic cancer through serine.
    Mengmeng Dong, Lidong Cao, Ranji Cui, Yingjun Xie.
      Pancreatic cancer is a kind of aggressive tumor famous for its lethality and intractability, and pancreatic ductal adenocarcinoma is the most common type. Patients with pancreatic cancer often suffer a rapid loss of weight and abdominal neuropathic pain in their early stages and then go through cachexia in the advanced stage. These features of patients are considered to be related to metabolic reprogramming of pancreatic cancer and abundant nerve innervation responsible for the pain. With increasing literature certifying the relationship between nerves and pancreatic ductal adenocarcinoma (PDAC), more evidence point out that innervation's role is not limited to neuropathic pain but explore its anti/pro-tumor functions in PDAC, especially the neural-metabolic crosstalks. This review aims to unite pancreatic cancer's innervation and metabolic rearrangements with terminated published articles. Hopefully, this article could explore the pathogenesis of PDAC and further promote promising detecting or therapeutic measurements for PDAC according to the lavish innervation in PDAC.
    Keywords:  cancer; innervation; malignant tumors; metabolic rearrangements; pancreatic
    DOI:  https://doi.org/10.3389/fonc.2022.992927
  5. Nat Commun. 2022 Dec 27. 13(1): 7965
    The lipid flippase SLC47A1 blocks metabolic vulnerability to ferroptosis.
    Zhi Lin, Jiao Liu, Fei Long, Rui Kang, Guido Kroemer, Daolin Tang, Minghua Yang.
      Ferroptosis is a type of regulated necrosis caused by unrestricted lipid peroxidation and subsequent plasma membrane rupture. However, the lipid remodeling mechanism that determines sensitivity to ferroptosis remains poorly understood. Here, we report a previously unrecognized role for the lipid flippase solute carrier family 47 member 1 (SLC47A1) as a regulator of lipid remodeling and survival during ferroptosis. Among 49 phospholipid scramblases, flippases, and floppases we analyzed, only SLC47A1 had mRNA that was selectively upregulated in multiple cancer cells exposed to ferroptotic inducers. Large-scale lipidomics and functional analyses revealed that the silencing of SLC47A1 increased RSL3- or erastin-induced ferroptosis by favoring ACSL4-SOAT1-mediated production of polyunsaturated fatty acid cholesterol esters. We identified peroxisome proliferator activated receptor alpha (PPARA) as a transcription factor that transactivates SLC47A1. The depletion of PPARA and SLC47A1 similarly sensitized cells to ferroptosis induction, whereas transfection-enforced re-expression of SLC47A1 restored resistance to ferroptosis in PPARA-deficient cells. Pharmacological or genetic blockade of the PPARA-SLC47A1 pathway increased the anticancer activity of a ferroptosis inducer in mice. These findings establish a direct molecular link between ferroptosis and lipid transporters, which may provide metabolic targets for overcoming drug resistance.
    DOI:  https://doi.org/10.1038/s41467-022-35707-2
  6. Nat Cancer. 2022 Dec 29.
    DUSP6 mediates resistance to JAK2 inhibition and drives leukemic progression.
    Tim Kong, Angelo B A Laranjeira, Kangning Yang, Daniel A C Fisher, LaYow Yu, Laure Poittevin De La Frégonnière, Anthony Z Wang, Marianna B Ruzinova, Jared S Fowles, Mary C Fulbright, Maggie J Cox, Hamza Celik, Grant A Challen, Sidong Huang, Stephen T Oh.
      Myeloproliferative neoplasms (MPNs) exhibit a propensity for transformation to secondary acute myeloid leukemia (sAML), for which the underlying mechanisms remain poorly understood, resulting in limited treatment options and dismal clinical outcomes. Here, we performed single-cell RNA sequencing on serial MPN and sAML patient stem and progenitor cells, identifying aberrantly increased expression of DUSP6 underlying disease transformation. Pharmacologic dual-specificity phosphatase (DUSP)6 targeting led to inhibition of S6 and Janus kinase (JAK)-signal transducer and activator of transcription (STAT) signaling while also reducing inflammatory cytokine production. DUSP6 perturbation further inhibited ribosomal S6 kinase (RSK)1, which we identified as a second indispensable candidate associated with poor clinical outcome. Ectopic expression of DUSP6 mediated JAK2-inhibitor resistance and exacerbated disease severity in patient-derived xenograft (PDX) models. Contrastingly, DUSP6 inhibition potently suppressed disease development across Jak2V617F and MPLW515L MPN mouse models and sAML PDXs without inducing toxicity in healthy controls. These findings underscore DUSP6 in driving disease transformation and highlight the DUSP6-RSK1 axis as a vulnerable, druggable pathway in myeloid malignancies.
    DOI:  https://doi.org/10.1038/s43018-022-00486-8
  7. NPJ Precis Oncol. 2022 Dec 27. 6(1): 95
    The landscape of therapeutic vulnerabilities in EGFR inhibitor osimertinib drug tolerant persister cells.
    Steven W Criscione, Matthew J Martin, Derek B Oien, Aparna Gorthi, Ricardo J Miragaia, Jingwen Zhang, Huawei Chen, Daniel L Karl, Kerrin Mendler, Aleksandra Markovets, Sladjana Gagrica, Oona Delpuech, Jonathan R Dry, Michael Grondine, Maureen M Hattersley, Jelena Urosevic, Nicolas Floc'h, Lisa Drew, Yi Yao, Paul D Smith.
      Third-generation EGFR tyrosine kinase inhibitors (EGFR-TKIs), including osimertinib, an irreversible EGFR-TKI, are important treatments for non-small cell lung cancer with EGFR-TKI sensitizing or EGFR T790M resistance mutations. While patients treated with osimertinib show clinical benefit, disease progression and drug resistance are common. Emergence of de novo acquired resistance from a drug tolerant persister (DTP) cell population is one mechanism proposed to explain progression on osimertinib and other targeted cancer therapies. Here we profiled osimertinib DTPs using RNA-seq and ATAC-seq to characterize the features of these cells and performed drug screens to identify therapeutic vulnerabilities. We identified several vulnerabilities in osimertinib DTPs that were common across models, including sensitivity to MEK, AURKB, BRD4, and TEAD inhibition. We linked several of these vulnerabilities to gene regulatory changes, for example, TEAD vulnerability was consistent with evidence of Hippo pathway turning off in osimertinib DTPs. Last, we used genetic approaches using siRNA knockdown or CRISPR knockout to validate AURKB, BRD4, and TEAD as the direct targets responsible for the vulnerabilities observed in the drug screen.
    DOI:  https://doi.org/10.1038/s41698-022-00337-w
  8. Pharmacol Res Perspect. 2023 Feb;11(1): e01047
    Autocrine EGF and TGF-α promote primary and acquired resistance to ALK/c-Met kinase inhibitors in non-small-cell lung cancer.
    Yueqin Wang, Yu Zhang, Ruiying Chen, Xin Tian.
      Drug resistance severely limits the clinical therapeutic value of molecularly targeted drugs. Growth factors gain a tremendous amount of focus due to the ability to promote drug resistance in non-small-cell lung cancer (NSCLC). However, whether tumor cells themselves can mediate drug resistance by secreting growth factors needs further clarification. Here, we first screened growth factors to identify autocrine epidermal growth factor (EGF) and transforming growth factor alpha (TGF-α) that caused primary resistance to the ALK inhibitor TAE684 in H3122 cells and the c-MET-specific inhibitor SGX-523 in EBC-1 cells. Next, we discovered increased autocrine production of EGF and TGF-α in established acquired resistant H3122/TR and EBC-1/SR cells. Importantly, overexpression of EGF and TGF-α in two NSCLC cell lines produced resistance to TAE684 and SGX-523. Clinically, NSCLC patients with high expression of EGF and TGF-α developed primary resistance to crizotinib. Mechanistically, autocrine EGF and TGF-α activated EGFR signaling pathways to survive targeted c-Met and ALK inhibition. Furthermore, combined treatment with gefitinib circumvented EGF- and TGF-α-mediated primary and acquired resistance to TAE684/SGX-523. Taken together, these results suggested increased autocrine EGF and TGF-α conferred primary and acquired resistance to ALK/c-Met kinase inhibitors in NSCLC.
    Keywords:  acquired resistance; autocrine growth factor; non-small-cell lung cancer; primary resistance
    DOI:  https://doi.org/10.1002/prp2.1047
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