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    • br Mechanisms of acquired resistance to

    2020-02-17


    Mechanisms of acquired resistance to 1st and 2nd generation EGFR inhibitors After treatment with first or second generation EGFR TKIs, virtually all patients after approximately 12 months develop acquired resistance (AR). Different mechanisms of AR to EGFR TKIs have been reported to date and may broadly divided in two subgroups: pharmacological and biological mechanisms, including alterations in the drug target, bypass track mechanisms, phenotypic/histologic changes and downstream signaling pathways alterations (Camidge et al., 2014, Lovly and Shaw, 2014). In 2005 two different groups first reported the development of a secondary mutation in the EGFR TK domain causing a substitution of a threonine with a methionine at the 790 site of the exon 20 (T790M mutation), leading to resistance to first generation EGFR TKI Gefitinib after initial response (Kobayashi et al., 2005a, Pao et al., 2005). The T790M mutation is the major mechanism of AR, since it is detected in vivo in approximately 41–62% of the cases at re-biopsy after acquired resistance to 1st generation EGFR TKIs (Hata et al., 2013, Kuiper et al., 2014, Sequist et al., 2011, Yu et al., 2013). Following preclinical ies reporting the development of T790M mutation even after irreversible EGFR TKIs (Godin-Heymann et al., 2008), a recent retrospective analysis confirmed T790M mutations as the major mechanism of AR, even in patients became resistant to the irreversible EGFR inhibitor Afatinib, with an overall frequency of ∼50% (Wu et al., 2016). The development of T790M is associated with AR to both 1st and 2nd generation EGFR TKIs by increasing the receptor affinity to the ATP and consequently limiting the potency of these ATP-competitive kinase inhibitors (Yun et al., 2008). The emergence of T790M mutations in Ac-IETD-AFC synthesis metastases is less frequent than extracranial sites (17% vs. 41% in a retrospective analysis), suggesting that other mechanisms of AR may be more relevant in the central nervous system (CNS), such as poor drug exposure (Hata et al., 2013). The identification of T790M mutation after AR to EGFR TKIs raised the question whether these mutations were the results of a selection process of pre-existing clones T790M+ due to the selective pressure of EGFR TKIs or were acquired during treatment because of novel genetic and epigenetic alterations (Suda et al., 2012). In favor of the “selection model” there are some preclinical and clinical evidences of the presence of pre-existing resistant clones before treatment, including T790M+, albeit their exact frequency and clinical significance is not yet fully understood (Maheswaran et al., 2008, Costa et al., 2014, Su et al., 2012, Ye et al., 2013, Yu et al., 2014, Lee et al., 2014). Indeed, preclinical data indicate that tumors with AR likely harbor mixed populations of drug-sensitive and drug-resistant cells with differential growth rates, with the T790M+ cells showing slower growth than T790M- ones (Chmielecki et al., 2011). These data are further supported by clinical evidences indicating a more indolent natural history and a longer post-progression survival among T790M harboring patients (Hata et al., 2013, Oxnard et al., 2011, Uramoto et al., 2012). In few cases the development of acquired resistance may involve the development of other rarer secondary mutations, including D761Y (Balak et al., 2006), L747S (Costa et al., 2007) and L854A (Bean et al., 2008). Acquisition of a secondary mutation is not the solely mechanism of AR to EGFR TKIs, but different preclinical and clinical studies, but EGFR-mutated tumors may escape the EGFR blockage in several other ways, including: Small Cell Lung Cancer (SCLC) transformation (2–14%) (Kuiper et al., 2014, Sequist et al., 2011, Yu et al., 2013, Niederst et al., 2015a), Epithelial to Mesenchimal Transition (EMT) (Sequist et al., 2011, Byers et al., 2013), MET amplification (4–5%) (Sequist et al., 2011, Yu et al., 2013, Takezawa et al., 2012), HER2 amplification (12–13%) (Yu et al., 2013, Takezawa et al., 2012), PIK3CA mutations (5%) (Sequist et al., 2011), AXL activation (Zhang et al., 2012), BRAF mutations (Ohashi et al., 2012), and NFkB activation (Bivona et al., 2011). In some instances, multiple mechanisms may operate simultaneously, albeit in the majority of cases seems to be mutually exclusive (Yu et al., 2013).