Targeting focal adhesion kinase overcomes erlotinib resistance in smoke induced lung cancer by altering phosphorylation of epidermal growth factor receptor

Hitendra S Solanki; Remya Raja; Alex Zhavoronkov; Ivan V Ozerov; Artem V Artemov; Jayshree Advani; Aneesha Radhakrishnan; Niraj Babu; Vinuth N Puttamallesh; Nazia Syed; Vishalakshi Nanjappa; Tejaswini Subbannayya; Nandini A Sahasrabuddhe; Arun H Patil; T S Keshava Prasad; Daria Gaykalova; Xiaofei Chang; Rachana Sathyendran; Premendu Prakash Mathur; Annapoorni Rangarajan; David Sidransky; Akhilesh Pandey; Evgeny Izumchenko; Harsha Gowda; Aditi Chatterjee

doi:10.18632/oncoscience.395

Targeting focal adhesion kinase overcomes erlotinib resistance in smoke induced lung cancer by altering phosphorylation of epidermal growth factor receptor

Oncoscience. 2018 Feb 23;5(1-2):21-38. doi: 10.18632/oncoscience.395. eCollection 2018 Jan.

Authors

Hitendra S Solanki^{1

2}, Remya Raja¹, Alex Zhavoronkov³, Ivan V Ozerov³, Artem V Artemov³, Jayshree Advani^{1

4}, Aneesha Radhakrishnan¹, Niraj Babu^{1

4}, Vinuth N Puttamallesh^{1

5}, Nazia Syed¹, Vishalakshi Nanjappa¹, Tejaswini Subbannayya¹, Nandini A Sahasrabuddhe¹, Arun H Patil^{1

2

6}, T S Keshava Prasad^{1

6

7}, Daria Gaykalova⁸, Xiaofei Chang⁸, Rachana Sathyendran⁹, Premendu Prakash Mathur², Annapoorni Rangarajan⁹, David Sidransky⁸, Akhilesh Pandey^{10

11

12

13}, Evgeny Izumchenko⁸, Harsha Gowda^{1

6}, Aditi Chatterjee^{1

6}

Affiliations

¹ Institute of Bioinformatics, International Tech Park, Bangalore 560066, India.
² School of Biotechnology, Kalinga Institute of Industrial Technology, Bhubaneswar, Odisha 751024, India.
³ Insilico Medicine, Inc., Emerging Technology Centers, Johns Hopkins University at Eastern, Baltimore, MD 21218, USA.
⁴ Manipal Academy of Higher Education, Manipal, Karnataka 576104, India.
⁵ School of Biotechnology, Amrita University, Kollam 690525, India.
⁶ Center for Systems Biology and Molecular Medicine, Yenepoya (Deemed to be University), Mangalore 575018, India.
⁷ NIMHANS-IOB Proteomics and Bioinformatics Laboratory, Neurobiology Research Centre, National Institute of Mental Health and Neurosciences, Bangalore 560029, India.
⁸ Department of Otolaryngology-Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA.
⁹ Department of Molecular Reproduction, Development and Genetics, Indian Institute of Science, Bangalore, 560012, India.
¹⁰ McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
¹¹ Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
¹² Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
¹³ Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.

Abstract

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.

Keywords: NSCLC; cigarette smoke; drug resistance; epidermal growth factor receptor; phosphoproteomics.

Abstract

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