Investigational EGFR-targeted therapies in HNSCC. Acquisition of EGFR TKI resistance and EMT phenotype is linked with activation of IGF1R/NF-κB pathway in EGFR-mutant NSCLC. Regulation of insulin sensitivity by serine/threonine phosphorylation of insulin receptor substrate proteins IRS1 and IRS2. The insulin receptor substrate (IRS) proteins: at the intersection of metabolism and cancer. Stem cell-like ALDH(bright) cellular states in EGFR-mutant non-small cell lung cancer: a novel mechanism of acquired resistance to erlotinib targetable with the natural polyphenol silibinin. A favourable prognostic marker for EGFR mutant non-small cell lung cancer: immunohistochemical analysis of MUC5B. Aurora kinase A drives the evolution of resistance to third generation EGFR inhibitors in lung cancer. Targeting FGFR overcomes EMT-mediated resistance in EGFR mutant non-small cell lung cancer. Reduction of PTEN protein and loss of epidermal growth factor receptor gene mutation in lung cancer with natural resistance to gefitinib (IRESSA). Rare cell variability and drug-induced reprogramming as a mode of cancer drug resistance. The cancer stem cell marker aldehyde dehydrogenase is required to maintain a drug-tolerant tumor cell subpopulation. AKT inactivation causes persistent drug tolerance to EGFR inhibitors. ER stress signaling promotes the survival of cancer ‘persister cells’ tolerant to EGFR tyrosine kinase inhibitors. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Persistence to anti-cancer treatments in the stationary to proliferating transition. Optimization of lag time underlies antibiotic tolerance in evolved bacterial populations. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. Second and third-generation epidermal growth factor receptor tyrosine kinase inhibitors in advanced nonsmall cell lung cancer. Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition. Treatment of staphylococcal infections with penicillin by intermittent sterilisation. Bacterial persistence as a phenotypic switch. Metrics other than potency reveal systematic variation in responses to cancer drugs. A chromatin-mediated reversible drug-tolerant state in cancer cell subpopulations. Single-cell analyses of transcriptional heterogeneity during drug tolerance transition in cancer cells by RNA sequencing. An epigenetic mechanism of resistance to targeted therapy in T cell acute lymphoblastic leukemia. Molecular mechanisms of epithelial–mesenchymal transition. Normal and neoplastic nonstem cells can spontaneously convert to a stem-like state. Stochastic state transitions give rise to phenotypic equilibrium in populations of cancer cells. Elucidation of drug-specific mechanisms that determine the degree and stability of cellular CTP may establish a framework for the elimination of cancer persisters, using new rationally designed drug combinations. Indeed, the first-in-class IRS1 inhibitor NT219 was highly synergistic with anti-epidermal growth factor receptor therapy across multiple in vitro and in vivo models. We found that differential serine/threonine phosphorylation of the insulin receptor substrate 1 (IRS1) protein determines the CTP of lung and of head and neck cancer cells under epidermal growth factor receptor inhibition, both in vitro and in vivo. This CTP is non-stochastic, determined pre-treatment and has a unimodal distribution ranging from 0 to almost 100%. Yet, we show here that cancer cells actually possess a highly stable inherited chance to persist (CTP) during therapy. Stochastic transition of cancer cells between drug-sensitive and drug-tolerant persister phenotypes has been proposed to play a key role in non-genetic resistance to therapy.
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