%0 Journal Article
%T Targeting focal adhesion kinase overcomes erlotinib resistance in smoke induced lung cancer by altering phosphorylation of epidermal growth factor receptor
%A Aditi Chatterjee
%A Akhilesh Pandey
%A Alex Zhavoronkov
%A Aneesha Radhakrishnan
%A Annapoorni Rangarajan
%A Artem V. Artemov
%A Arun H. Patil
%A Daria Gaykalova
%A David Sidransky
%A Evgeny Izumchenko
%A Harsha Gowda
%A Hitendra S. Solanki
%A Ivan V. Ozerov
%A Jayshree Advani
%A Nandini A. Sahasrabuddhe
%A Nazia Syed
%A Niraj Babu
%A Premendu Prakash Mathur
%A Rachana Sathyendran
%A Remya Raja
%A T.S. Keshava Prasad
%A Tejaswini Subbannayya
%A Vinuth N. Puttamallesh
%A Vishalakshi Nanjappa
%A Xiaofei Chang
%J Archive of "Oncoscience".
%D 2018
%R 10.18632/oncoscience.395
%X EGFR-based targeted therapies have shown limited success in smokers. Identification of alternate signaling mechanism(s) leading to TKI resistance in smokers is critically important. We observed increased resistance to erlotinib in H358 NSCLC (non-small cell lung carcinoma) cells chronically exposed to cigarette smoke (H358-S) compared to parental cells. SILAC-based mass-spectrometry approach was used to study altered signaling in H358-S cell line. Importantly, among the top phosphosites in H358-S cells we observed hyperphosphorylation of EGFR (Y1197) and non-receptor tyrosine kinase FAK (Y576/577). Supporting these observations, a transcriptomic-based pathway activation analysis of TCGA NSCLC datasets revealed that FAK and EGFR internalization pathways were significantly upregulated in smoking patients, compared to the never-smokers and were associated with elevated PI3K signaling and lower level of caspase cascade and E-cadherin pathways activation. We show that inhibition of FAK led to decreased cellular proliferation and invasive ability of the smoke-exposed cells, and restored their dependency on EGFR signaling. Our data suggests that activation of focal adhesion pathway significantly contributes to erlotinib resistance, and that FAK is a potential therapeutic target for management of erlotinib resistance in smoke-induced NSCLC
%K cigarette smoke
%K epidermal growth factor receptor
%K NSCLC
%K phosphoproteomics
%K drug resistance
%U https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5854290/