Amplification of CRKL induces transformation and EGFR inhibitor resistance in human non small cell lung cancers
Cette étude montre que la surexpression du gène CRKL, situé sur le chromosome 22q11.21, est associée à la résistance à une thérapie ciblée anti-EGFR dans le cancer du poumon non à petites cellules
We previously characterized copy number alterations in a large collection of primary lung adenocarcinomas and identified a region of recurrent amplification on chromosome 22q11.21 in a subset of samples. CRKL is located within this recurrently amplified peak region and encodes for an adaptor protein composed of one SH2 and two SH3 domains. Here we show that CRKL is amplified and overexpressed in non-small cell lung cancer (NSCLC) cells that harbor amplifications of 22q11.21. Overexpression of CRKL in immortalized human airway epithelial cells at levels comparable to that observed in lung cancer cells promoted anchorage independent growth and rendered immortalized human airway epithelial cells tumorigenic. Oncogenic CRKL interacts with SOS1 and C3G, resulting in activation of the SOS1-RAS-RAF-ERK and SRC-C3G-RAP1 pathways. Suppression of CRKL expression in NSCLC cells that harbor CRKL amplifications selectively induced cell death that can be partially rescued by constitutively active RAP1. Overexpression of CRKL in EGFR mutant cells induces resistance to gefitinib by activating SOS1-dependent MAPK and p85-dependent AKT signaling. We identified CRKL amplification in an EGFR inhibitor treated lung adenocarcinoma that was not present prior to treatment. These observations show that overexpression of CRKL induces cell transformation by activating RAS and RAP1 signaling, credential CRKL as a therapeutic target for a subset of NSCLC that harbor CRKL amplifications and implicate CRKL as an additional mechanism of resistance to EGFR-directed therapy.