AXL/CDCP1/SRC axis confers acquired resistance to osimertinib in lung cancer

• Published in: Scientific reports Vol. 12; no. 1; p. 8983
• Main Authors: Murakami, Yuichi, Kusakabe, Daiki, Watari, Kosuke, Kawahara, Akihiko, Azuma, Koichi, Akiba, Jun, Taniguchi, Masahiko, Kuwano, Michihiko, Ono, Mayumi
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 28.05.2022; Nature Publishing Group UK; Nature Portfolio
• Subjects: Acrylamides; AKT protein; Aniline Compounds; Antigens, Neoplasm - therapeutic use; Axl protein; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Carcinoma, Non-Small-Cell Lung - pathology; Cell Adhesion Molecules - genetics; Drug Resistance, Neoplasm - genetics; Enzyme inhibitors; Epidermal growth factor receptors; ErbB Receptors - metabolism; Humans; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Lung Neoplasms - pathology; Mutation; Non-small cell lung carcinoma; Phosphorylation; Protein Kinase Inhibitors - pharmacology; Protein Kinase Inhibitors - therapeutic use; Proto-Oncogene Proteins c-akt - genetics; Small cell lung carcinoma; src-Family Kinases - genetics; Targeted cancer therapy; Tumor cell lines; Tumors
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-022-12995-8

Osimertinib, a third-generation EGFR-TKI, has nowadays been applied to non-small cell lung cancer harboring activated EGFR mutation with or without T790M, but ultimately develop resistance to this drug. Here we report a novel mechanism of acquired resistance to osimertinib and the reversal of which could improve the clinical outcomes. In osimertinib-resistant lung cancer cell lines harboring T790M mutation that we established, expression of multiple EGFR family proteins and MET was markedly reduced, whereas expression of AXL, CDCP1 and SRC was augmented along with activation of AKT. Surprisingly, AXL or CDCP1 expression was induced by osimertinib in a time-dependent manner up to 3 months. Silencing of CDCP1 or AXL restored the sensitivity to osimertinib with reduced activation of SRC and AKT. Furthermore, silencing of both CDCP1 and AXL increased the sensitivity to osimertinib. Either silencing of SRC or dasatinib, a SRC family kinase (SFK) inhibitor, suppressed AKT phosphorylation and cell growth. Increased expression of AXL and CDCP1 was observed in refractory tumor samples from patients with lung cancer treated with osimertinib. Together, this study suggests that AXL/SFK/AKT and CDCP1/SFK/AKT signaling pathways play some roles in acquired osimertinib resistance of non-small cell lung cancer.