C-MET inhibitors for advanced non-small cell lung cancer

Pasquini, Giulia; Giaccone, Giuseppe

doi:10.1080/13543784.2018.1462336

Cited by 88 publications

(70 citation statements)

References 69 publications

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“…Interestingly, inhibition of autophagy consistently led to re-sensitization to c-Met inhibitors during EMT. The c-Met oncogene is one of the two most highly mutated tyrosine kinase receptors in NSCLC, and resistance to tyrosine kinase inhibitors (TKI) invariably follows after treatment [56]. Indeed, resistance to erlotinib is common in lung cancer, and ATG16L1 knockdown re-sensitized cells to increased EMT-induced erlotinib resistance.…”

Section: Discussionmentioning

confidence: 99%

An integrative systems biology and experimental approach identifies convergence of epithelial plasticity, metabolism, and autophagy to promote chemoresistance

Ware

Ding

et al. 2018

Preprint

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26The evolution of therapeutic resistance is a major cause of death for patients with solid 27 tumors. The development of therapy resistance is shaped by the ecological dynamics 28 within the tumor microenvironment and the selective pressure induced by the host 29 immune system. These ecological and selective forces often lead to evolutionary 30 convergence on one or more pathways or hallmarks that drive progression. These 31 hallmarks are, in turn, intimately linked to each other through gene expression 32 networks. Thus, a deeper understanding of the evolutionary convergences that occur at 33 the gene expression level could reveal vulnerabilities that could be targeted to treat 34 therapy-resistant cancer. To this end, we used a combination of phylogenetic clustering, 35 systems biology analyses, and wet-bench molecular experimentation to identify 36 convergences in gene expression data onto common signaling pathways. We applied 37 these methods to derive new insights about the networks at play during TGF-β-38 mediated epithelial-mesenchymal transition in a lung cancer model system. 39Phylogenetics analyses of gene expression data from TGF-β treated cells revealed 40 evolutionary convergence of cells toward amine-metabolic pathways and autophagy 41 during TGF-β treatment. Using high-throughput drug screens, we found that 42 knockdown of the autophagy regulatory, ATG16L1, re-sensitized lung cancer cells to 43 cancer therapies following TGF-β-induced resistance, implicating autophagy as a TGF-β-44 mediated chemoresistance mechanism. Analysis of publicly-available clinical data sets 45 validated the adverse prognostic importance of ATG16L expression in multiple cancer 46 types including kidney, lung, and colon cancer patients. These analyses reveal the 47 usefulness of combining evolutionary and systems biology methods with experimental 48 validation to illuminate new therapeutic vulnerabilities. 49 50

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Section: Discussionmentioning

confidence: 99%

An integrative systems biology and experimental approach identifies convergence of epithelial plasticity, metabolism, and autophagy to promote chemoresistance

Ware

Ding

et al. 2018

Preprint

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“…Small molecule inhibitors of MET have been generated that target the ATP binding pocket [131,132]. These molecules are known as Class I and Class II.…”

Section: Hepatocyte Growth Factor Receptor (Hfgr C-met)mentioning

confidence: 99%

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

Hamid

Petreaca

2020

Cancers

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Secondary resistant mutations in cancer cells arise in response to certain small molecule inhibitors. These mutations inevitably cause recurrence and often progression to a more aggressive form. Resistant mutations may manifest in various forms. For example, some mutations decrease or abrogate the affinity of the drug for the protein. Others restore the function of the enzyme even in the presence of the inhibitor. In some cases, resistance is acquired through activation of a parallel pathway which bypasses the function of the drug targeted pathway. The Catalogue of Somatic Mutations in Cancer (COSMIC) produced a compendium of resistant mutations to small molecule inhibitors reported in the literature. Here, we build on these data and provide a comprehensive review of resistant mutations in cancers. We also discuss mechanistic parallels of resistance.

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“…To date, there are no clinical studies of 18 F-FLT PET/CT of novel targeted therapiesin assessing early response in lung cancer. c-MET inhibitors, have the potential to benefit subsets of lung cancer patients with specific genetic alterations [16]. Exon-14 skipping mutations appear so far to be the most promising molecular subset that is sensitive to c-MET inhibitors, whereas overexpression, amplification, and point mutations of MET seem more challenging subgroups to target [17].…”

Section: Introductionmentioning

confidence: 99%

Early Response Assessment to Targeted Therapy Using 3′-deoxy-3′[(18)F]-Fluorothymidine (18F-FLT) PET/CT in Lung Cancer

et al. 2020

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Although 2-deoxy-2-[18F]-fluoro-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) is a sensitive nuclear medicine modality, specificity for characterizing lung cancer is limited. Tumor proliferation and early response to molecularly targeted therapy could be visualized using 3′-deoxy-3′[(18)F]-fluorothymidine (18F-FLT) PET/CT. The superiority of 18F-FLT PET/CT over 18F-FDG PET/CT in early therapeutic monitoring has been well described in patients after chemotherapy, radiotherapy, and/or chemo/radiotherapy. In thispilot study, we explorethe use of 18F-FLT PET/CT as an early response evaluation modality in patients with lung cancerand provide specific case studies of patients with small cell lung cancer and non-small cell lung cancer who received novel targeted therapies. Early response for c-MET inhibitor was observed in four weeks and for MDM2 inhibitor in nine days.

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C-MET inhibitors for advanced non-small cell lung cancer

Cited by 88 publications

References 69 publications

An integrative systems biology and experimental approach identifies convergence of epithelial plasticity, metabolism, and autophagy to promote chemoresistance

An integrative systems biology and experimental approach identifies convergence of epithelial plasticity, metabolism, and autophagy to promote chemoresistance

Secondary Resistant Mutations to Small Molecule Inhibitors in Cancer Cells

Early Response Assessment to Targeted Therapy Using 3′-deoxy-3′[(18)F]-Fluorothymidine (18F-FLT) PET/CT in Lung Cancer

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