TGF-β IL-6 axis mediates selective and adaptive mechanisms of resistance to molecular targeted therapy in lung cancer
Zhan Yao,Silvia Fenoglio,Dingcheng Gao,Matthew Camiolo,Brendon M. Stiles,Trine Lindsted,Michaela Schlederer,Christopher Johns,Nasser K. Altorki,Vivek Mittal,Lukas Kenner,Raffaella Sordella +11 more
TLDR
It is argued that both tumor cell-autonomous mechanisms and/or activation of the tumor microenvironment could contribute to primary and acquired erlotinib resistance, and as such, treatments based on EGFR inhibition may not be sufficient for the effective treatment of lung-cancer patients harboring mutant EGFR.Abstract:
The epidermal growth-factor receptor (EGFR) tyrosine kinase inhibitor erlotinib has been proven to be highly effective in the treatment of nonsmall cell lung cancer (NSCLC) harboring oncogenic EGFR mutations. The majority of patients, however, will eventually develop resistance and succumb to the disease. Recent studies have identified secondary mutations in the EGFR (EGFR T790M) and amplification of the N-Methyl-N′-nitro-N-nitroso-guanidine (MNNG) HOS transforming gene (MET) oncogene as two principal mechanisms of acquired resistance. Although they can account for approximately 50% of acquired resistance cases together, in the remaining 50%, the mechanism remains unknown. In NSCLC-derived cell lines and early-stage tumors before erlotinib treatment, we have uncovered the existence of a subpopulation of cells that are intrinsically resistant to erlotinib and display features suggestive of epithelial-to-mesenchymal transition (EMT). We showed that activation of TGF-β–mediated signaling was sufficient to induce these phenotypes. In particular, we determined that an increased TGF-β–dependent IL-6 secretion unleashed previously addicted lung tumor cells from their EGFR dependency. Because IL-6 and TGF-β are prominently produced during inflammatory response, we used a mouse model system to determine whether inflammation might impair erlotinib sensitivity. Indeed, induction of inflammation not only stimulated IL-6 secretion but was sufficient to decrease the tumor response to erlotinib. Our data, thus, argue that both tumor cell-autonomous mechanisms and/or activation of the tumor microenvironment could contribute to primary and acquired erlotinib resistance, and as such, treatments based on EGFR inhibition may not be sufficient for the effective treatment of lung-cancer patients harboring mutant EGFR.read more
Citations
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Cancer drug resistance: an evolving paradigm
TL;DR: There are now unprecedented opportunities to understand and overcome drug resistance through the clinical assessment of rational therapeutic drug combinations and the use of predictive biomarkers to enable patient stratification.
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Epithelial-to-mesenchymal transition is not required for lung metastasis but contributes to chemoresistance
Kari R. Fischer,Anna Durrans,Sharrell Lee,Jianting Sheng,Fuhai Li,Stephen T. C. Wong,Hyejin Choi,Tina El Rayes,Seongho Ryu,Seongho Ryu,Juliane S. Troeger,Robert F. Schwabe,Linda T. Vahdat,Nasser K. Altorki,Vivek Mittal,Dingcheng Gao +15 more
TL;DR: The potential of an EMT-targeting strategy, in conjunction with conventional chemotherapies, for breast cancer treatment is suggested, using a mesenchymal-specific Cre-mediated fluorescent marker switch system in spontaneous breast-to-lung metastasis models.
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The quest to overcome resistance to EGFR-targeted therapies in cancer
TL;DR: A comprehensive review of resistance pathways to EGFR-targeted therapies in lung, colorectal and head and neck cancers is presented and therapeutic strategies that are designed to circumvent resistance are discussed.
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Understanding and targeting resistance mechanisms in NSCLC.
Julia K Rotow,Trever G. Bivona +1 more
TL;DR: Common mechanistic themes underpinning resistance to targeted therapies that are shared by NSCLC subtypes are highlighted, including those with oncogenic alterations in epidermal growth factor receptor, anaplastic lymphoma kinase (ALK), ROS1 proto-oncogene receptor tyrosine kinase, serine/threonine-protein kinase b-raf (BRAF) and other less established oncoproteins.
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The lung microenvironment: an important regulator of tumour growth and metastasis
Nasser K. Altorki,Geoffrey J. Markowitz,Dingcheng Gao,Jeffrey L. Port,Ashish Saxena,Brendon M. Stiles,Timothy E. McGraw,Vivek Mittal +7 more
TL;DR: How the tumour-reprogrammed lung microenvironment can contribute to primary lung tumour progression as well as lung metastasis from extrapulmonary neoplasms by promoting inflammation, angiogenesis, immune modulation and therapeutic responses is discussed.
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TL;DR: First-line gefitinib for patients with advanced non-small-cell lung cancer who were selected on the basis of EGFR mutations improved progression-free survival, with acceptable toxicity, as compared with standard chemotherapy.
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MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling
Jeffrey A. Engelman,Kreshnik Zejnullahu,Tetsuya Mitsudomi,Youngchul Song,Courtney Hyland,Joon Oh Park,Neal I. Lindeman,Christopher-Michael Gale,Xiaojun Zhao,James J. Christensen,Takayuki Kosaka,Alison J. Holmes,Andrew M. Rogers,Federico Cappuzzo,Tony Mok,Charles Lee,Bruce E. Johnson,Lewis C. Cantley,Pasi A. Jänne +18 more
TL;DR: It is proposed that MET amplification may promote drug resistance in other ERBB-driven cancers as well after it was found that amplification of MET causes gefitinib resistance by driving ERBB3 (HER3)–dependent activation of PI3K, a pathway thought to be specific to EGFR/ERBB family receptors.
Journal ArticleDOI
EGF receptor gene mutations are common in lung cancers from “never smokers” and are associated with sensitivity of tumors to gefitinib and erlotinib
William Pao,Vincent A. Miller,Maureen F. Zakowski,Jennifer Doherty,Katerina Politi,Inderpal S. Sarkaria,Bhuvanesh Singh,Robert T. Heelan,Valerie W. Rusch,Lucinda Fulton,Elaine R. Mardis,Doris M. Kupfer,Richard K. Wilson,Mark G. Kris,Harold E. Varmus +14 more
TL;DR: Data show that adenocarcinomas from never smokers comprise a distinct subset of lung cancers, frequently containing mutations within the TK domain of EGFR that are associated with gefitinib and erlotinib sensitivity.
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