Abstract A18: Reduced NF1 expression in resistance to EGF receptor inhibitory drugs in lung adenocarcinoma

Abstract

Abstract Tyrosine kinase inhibitors, such as erlotinib, exhibit striking efficacy in lung adenocarcinomas with activating mutations in the epidermal growth factor receptor (EGFR). However, patients inevitably develop therapeutic resistance, often due to second site mutations (T790M) in the EGFR. In this study, we aim to identify novel determinants of resistance in order to find new drug targets that may increase the effectiveness of EGFR targeted therapy. We performed a genome-wide siRNA screen using the PC9 cell line, which harbors an EGFR exon 19 deletion mutation and is exquisitely sensitive to erlotinib. From this screen, we identified genes that upon knockdown had a significantly different effect on cell survival in drug-treated versus untreated conditions. Within the list of candidate genes is the tumor suppressor NF1, encoding the RAS GTPase-activating protein neurofibromin. In addition, low Nf1 expression is associated with the acquisition of resistance in a preclinical mouse model of activated mutant EGFR-driven lung cancer in tumors where the second site mutation in EGFR did not occur. In vitro experiments show that decreased expression of NF1 results in a failure of erlotinib to fully inhibit RAS-ERK signaling. Treatment of NF1-deficient lung cancer cells with a MEK inhibitor restored their sensitivity to erlotinib both in in vitro and in xenograft experiments. Interestingly, approximately half of the erlotinib resistant tumors in our mouse model regressed upon treatment with erlotinib in combination with a MEK inhibitor, while tumors treated with erlotinib only continued to progress. This suggests that combination of a MEK inhibitor and an EGFR inhibitor may be an effective approach to the treatment of some cases of drug resistant lung cancer.