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• W4224000867 abstract "ABSTRACT Drug-tolerant “dormant” cells (DTC) have emerged as one of the major non-genetic mechanisms driving resistance to targeted therapy in lung cancer, although the sequence of events leading to entry and exit from dormancy remain poorly described. Here, we performed real-time monitoring of the cell cycle dynamics during the adaptive response to Epidermal Growth Factor Receptor tyrosine kinase inhibitors (EGFR-TKi) in a panel of EGFR-mutated lung cancer cell lines. We identified a rare population of S/G2 cycling cells (referred to as early escapers) that emerged in the first hours of treatment amongst stably arrested and progressively dying G1 cells. We determined that early escapers evolved from a non-proliferative differentiated alveolar type 1 (AT1) phenotype which was invariably associated with cytoskeletal remodeling through Rho/ROCK pathway activation. Using a panel of Rho-pathway inhibitors, we found that the farnesyltransferase inhibitor tipifarnib induced a complete clearance of EGFR-TKi-induced DTC thus fully preventing relapse in vitro . Using a xenograft model and a PDX model of EGFR L858R/T790M lung cancer, co-treatment with tipifarnib prevented relapse to osimertinib for up to 6 months with no evidence of toxicity. Among the farnesylated proteins regulated during osimertinib treatment, concomitant inhibition of RHOE and LaminB1 was sufficient to recapitulated FTIs’ effect. Osimertinib and tipifarnib co-treatment completely suppressed the emergence of AT1 phenotype, prevented mitosis of S/G2-treated cells and increased the apoptotic response through activation of ATF4-CHOP-dependent Integrated Stress Response (ISR) pathway. Our data strongly support the use of tipifarnib in combination with osimertinib in patients to effectively and durably prevent relapse." @default.
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• W4224000867 date "2022-04-03" @default.
• W4224000867 modified "2023-10-18" @default.
• W4224000867 title "Farnesyltransferase inhibition overcomes the adaptive resistance to osimertinib in EGFR-mutant NSCLC" @default.
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• W4224000867 doi "https://doi.org/10.1101/2022.04.01.486707" @default.
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