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  • The development of C S

    2021-01-15

    The development of C797S mutation has been reported in vivo in a small cohort (15 subjects) of EGFR T790M positive patients progressing after Osimertinib: this tertiary mutation was found, using a droplet digital PCR (ddPCR) assay, in 40% of patients after AR to this agent, while 33% of the cases exhibited persistence of the secondary mutation T790M (without C797S) and 27% showed neither T790M nor C797S mutations (Thress et al., 2015). The development of C797S has been recently confirmed in vivo in tumor samples obtained after re-biopsy in patients with acquired resistance to Osimertinib (Yu et al., 2015) and Olmutinib (Song et al., 2015) and in plasma samples from patients with AR to Rociletinib, albeit with a less frequency than observed with Osimertinib (2% vs. 32%), suggesting a distinct pattern of resistance mechanisms (Chabon et al., 2016). Jia et al. recently identified an investigational compound, EAI045, that targets selected drug-resistant EGFR mutants but spares the wild-type receptor. Unlike 3rd generation mutant-selective EGFR TKIs, this Caspase-6 Colorimetric Assay Kit binds to T790M-mutant EGFR in an allosteric site created by the displacement of the regulatory C-helix in an inactive conformation of the kinase. This different mechanism of action do not allow an efficient EGFR blockage as single agent, but a marked synergy was observed with the anti-EGFR antibody Cetuximab in mouse models of lung cancer driven by L858R/T790M EGFR and, interestingly, by L858R/T790M/C797S EGFR (Jia et al., 2016). Studying 32 cell lines with acquired resistance to several EGFR TKIs, including Gefitinib, Afatinib, WZ4002 and Osimertinib, Eberlein et al. reported that resistance to AZD9291 and other EGFR inhibitors in vitro is often associated with increased dependence on RAS signaling, through NRAS mutations (including the novel E63K NRAS mutation) and KRAS gain, and sensitivity to the MEK inhibitor Selumetinib (Eberlein et al., 2015). These data are in line with previous reports indicating the RAS-MAPK signaling pathway as an alternative mechanisms of acquired resistance to EGFR inhibitors in both lung and colon cancer (Misale et al., 2014) in many different ways, including loss of NF1 (de Bruin et al., 2014a), CRKL amplification (Cheung et al., 2011), MAPK1 amplification (Ercan et al., 2012). Moreover, the combination of Osimertinib and Selumetinib delayed the emergence of resistance in EGFRm and EGFRm/T790M cells (Eberlein et al., 2015). These data provide the rationale for concomitant use of Osimertinib and Selumetinib in the ongoing multi-arm phase Ib trial TATTON [NCT02143466]. Activation of alternative signaling pathways in an EGFR-independent way, may also occur after acquired resistance to Osimertinib. Planchard et al. recently reported the amplification of HER2 and MET (not present in the pre-treatment specimens), respectively, in two patients enrolled into the phase I AURA trial in re-biopsy specimens collected at the AR to this mutant-selective TKI with disappearance of the T790M mutation and no other additional mutations (Planchard et al., 2015). In a small case series of 4 EGFR exon 19 del/T790M NSCLCs patients with acquired resistance to Osimertinib enrolled into the AURA trial, re-biopsy after AR revealed the presence of different mechanisms of resistance: none of the 4 patients developed C797S mutation, but loss of EGFR T790M mutation was observed in addition to alternative pathways activation, including FGFR1 amplification, PTEN deletion, MAPK1 and AKT3 overexpression, and histologic transformation (i.e. SCLC transition) (Kim et al., 2015), confirming previous in vitro findings (Cross et al., 2014, Ercan et al., 2012, Tabara et al., 2012, Ware et al., 2013). Similarly to a previous report (Niederst et al., 2015a), SCLC transformation was associated with RB loss. This small case series conducted on patients progressing after both 1st and 3rd generation EGFR TKIs confirms the complexity and substantial overlay of mechanisms of acquired resistance, under the selective pressure of different classes EGFR TKIs.