Overcoming MET-mediated resistance in oncogene-driven NSCLC

•MET overexpression provokes targeted therapy resistance in NSCLC•Tissue biopsies surpass liquid ones detecting MET-mediated resistance•MET overexpression, a potential driver, warrants deeper study•MET or SHP2 inhibitors can effectively tackle This study evaluates the efficacy of combining therapies with MET to overcome different NSCLC subtypes. A prevalence was conducted for amplification and samples from patients who relapsed on ALK, ROS1, RET tyrosine kinase inhibitors. detected 37.5% tissue biopsies, which allow detection compared 7.4% biopsies. The development drug by confirmed EGFRex19del-, KRASG12C-, HER2ex20ins-, TPM3-NTRK1-mutant cell lines. combination found both vitro vivo assays. highlights importance considering as driver better identify could potentially benefit approaches Targeted have become standard treatment oncogene-driven non-small lung cancer (NSCLC),1Rosell R. Karachaliou N. 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Consequently, numbers, levels, tumor cytological (TBx) (LBx) 28 had disease (n = 15), 8) 5) TKIs. For 20 only LBx were available, one TBx available remaining seven least (blood, cerebrospinal fluid, pleural effusion) (Table S1). analyzed next generation sequencing (NGS) fluorescence situ hybridization (FISH), determined nCounter, investigated immunohistochemistry (IHC). LBx, NGS 2/27 (7.4%) (Figure 1A Table Both (P6 P27) (variant 3) lorlatinib. TBx, 3/8 (37.5%) Two them (P24 1) progressing NGS, P24 displaying IHC. Patient P27 (pleural effusion), (blood) result negative amplification. third (P26) CD74-ROS1-rearranged crizotinib IHC without 1B). Our demonstrates higher percentage than (7.4%). Nonetheless, ease practice time needs be acknowledged seen fact 27/28 analyze. However, frequently missed TBx. Moreover, use allows help further TKI may treatment. To explore functional role defined genetic background generated stable lines using lentiviral transduction wild-type dynamically overexpressed doxycycline-inducible manner (tetON-MET cells). Five (EGFRex19del-mutant: HCC827, KRASG12C-mutant: NCI-H358, HER2ex20ins-mutant: NCI-H1781; EML4-ALK-mutant: NCI-H2228, SLC34A2-ROS1-mutant: HCC-78) colorectal line (TPM3-NTRK1-mutant: KM12) selected model systems. Overexpression 170 kDa immature pro-MET all Western blot 2A ). It reported cleavage into 50 α-subunit 145 β-subunit not required activity, uncleaved precursor still constitutively active.27Zhang Babic Regulation oncogene: mechanisms.Carcinogenesis. 345-355https://doi.org/10.1093/carcin/bgw015Crossref (57) Likewise, increased Y1234/1235 MET-overexpressing cells, suggesting sufficient MET-receptor self-activation. exclude fetal calf serum (FCS)-dependent KM12 cells absence FCS S1A). Doxycycline led strong enhancement activating site independently supplementation, self-activation overexpression. Next, examined treating their corresponding 2B). osimertinib, KRASG12C sotorasib, poziotinib, alectinib NTRK-/ROS1 entrectinib used. While sensitive therapy, doxycycline-induced caused sotorasib HCC827 NCI-H358 respectively. NCI-H1781 partial poziotinib entrectinib, respectively, observed. contrast, did alter sensitivity NCI-H2228 HCC-78 We tested whether achieved multiplicity infection (MOI), would confer cells. although displayed phosphorylation, resistant S1B). Changes excluded comparing behavior transfected doxycycline parental S2A). viability assay results, NCI-H1781, demonstrated morphological changes upon S2B). counterparts grew epithelial clusters, exhibited mesenchymal spindle-like shape single movement. explored direct simultaneous blockade four recapitulating MET-driven (HCC827, combined blot. Upon single-treatment stronger AKT, ERK, STAT3 overexpressing endogenous 3A These indicate MAPK/PI3K downstream support observation development. lines, agent either decreased AKT ERK more potently agents alone, reversion inhibition, since known negatively regulate activity.28Mohrherr Uras I.Z. Moll H.P. Casanova STAT3: versatile functions cancer.Cancers. 12: 1107https://doi.org/10.3390/cancers12051107Crossref (40) 3B). pronounced nearly abolished but resulted minor decrease 3A). Yet, alone. Thus, suggest efficacious overcoming capmatinib M674824Pudelko (Figures 4A S3). As already suggested analyses, reverting synergism between dose matrices Loewe method29Loewe problem antagonism drugs.Arzneimittelforschung. 1953; 3: 285-290PubMed S4). Similar obtained colony formation assays 4B). prevented MET, forming ability conferred small reduced count Finally, adding revert this, KRASG12C-mutant sotorasib. Mice subcutaneously injected tetON-MET fed doxycycline-containing diet establish induction autophosphorylation xenograft S5A). Tumor bearing mice kept during experiment randomized 10/group) receive once daily oral treatments vehicle control, monotherapy two 75 days. Sotorasib delayed volumes reaching humane endpoint days 5A significantly inhibited regression treated animals 5B). supported lysates end S5B). tolerated based body weight change 5C) symptoms. date, best predictive biomarkers METex14 mutation amplification.9Paik Scholar,30Le Paz-Ares L.G. Cabrera Galvez Vicente Baz Y.-C. Kang J.-H. Schumacher K.-M. (pts) (NSCLC) (METamp).J. 9021https://doi.org/10.1200/JCO.2021.39.15_suppl.9021Crossref mostly primary NSCLC.13Camidge Increasing suggests dysregulated ALK,17Dagogo-Jack ROS1,18Yang oncogene agnostic indicates occur relapse therapies.31Doebele R.C. Acquired agnostic.Cancer Cell. 36: 347-349https://doi.org/10.1016/j.ccell.2019.09.011Abstract Most focused through FISH evaluated, particularly earlier mixed terms efficacy,32Hirsch F.R. Zvirbule Braiteh Rittmeyer Belda-Iniesta Isla Cosgriff Boyer Ueda al.Efficacy II, placebo-controlled onartuzumab platinum-doublet squamous Lung Cancer. 2017; 18: 43-49https://doi.org/10.1016/j.cllc.2016.05.011Abstract (25) quite exploratory.33Ruiz Garibay Roch Garrido Lopez Aguado Callejo Perez Marse Fabregat Garcia Campelo M.R. Blasco Cordellat Sanchez Torres J.M. al.1010P Assessment early spatial transcriptomics.Ann. S1015-S1016https://doi.org/10.1016/j.annonc.2022.07.1136Abstract complex machinery transcription, translation, degradation determining abundance34Vogel Marcotte E.M. Insights regulation p