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Targeting Focal Adhesion Kinase overcomes erlotinib resistance in smoke induced lung cancer by altering phosphorylation of Epidermal Growth Factor Receptor

ABSTRACT: Cigarette smoking is the leading cause for non-small cell lung carcinoma (NSCLC). Tyrosine kinase inhibitors (TKIs) targeting EGFR are in clinical practice and has benefitted patients with EGFR mutations. However, EGFR based targeted therapies have shown limited success in smokers. Identification of alternate signaling mechanism(s) leading to TKI resistance in smokers is critical for developing novel therapies for lung cancer. We observed increased resistance to erlotinib in H358 lung cancer cells exposed to cigarette smoke (H358-S) compared to parental cells. To systematically identify signaling pathways that could potentially confer resistance to erlotinib, we carried out stable isotope labeling by amino acids in cell culture (SILAC)-based phosphotyrosine analysis of H358-S and parental cells. We identified 238 unique phosphosites, of which 111 phosphosites were hyperphosphorylated (≥ 2-fold¬¬¬¬¬¬) in H358 -S cells. Importantly, we observed hyperphosphorylation of EGFR at Y1197 and non-receptor tyrosine kinases, including FAK and FRK in H358-S cells. Inhibition of FAK with its inhibitor PF-562271 led to decreased cellular proliferation and invasive ability of the smoke exposed cells. Further, we observed that treatment with PF-562271 could restore dependency of H358-S cells on EGFR signaling.

INSTRUMENT(S): LTQ Orbitrap Velos

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Lung

DISEASE(S): Non-small Cell Lung Carcinoma

SUBMITTER: Aditi Chatterjee

LAB HEAD: Aditi Chatterjee

PROVIDER: PXD006705 | Pride | 2018-03-21

REPOSITORIES: Pride

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			Action	DRS
	H358_CSC_SILAC_pY1000_121713_1.raw	Raw
	H358_CSC_SILAC_pY1000_121713_1_PD1.4_Sequest_Mascot_122313.msf	Msf
	H358_CSC_SILAC_pY1000_121713_1_PD1.4_Sequest_Mascot_122313.pep.xml	Pepxml
	H358_CSC_SILAC_pY1000_121713_1_PD1.4_Sequest_Mascot_122313.prot.xml	Xml

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

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

Oncoscience 20180101 1-2

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- ...[more]

PMID: 29556515

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Project description:Although smoking-induced lung disease tends to be more common in the upper lobe, it is not known if this results from the skewed distribution of inhaled cigarette smoke or increased susceptibility of the upper lobes to these disorders. The distribution of inhaled cigarette smoke within the lung is complex, depending on lung pressure-volume relationships, gravity, individual smoking habits and the properties of the individual components of cigarette smoke. With the knowledge that the small airway epithelium is the earliest site of smoking-induced lung disease, and that the small airway epithelium is acutely sensitive to inhaled cigarette smoke with significant changes in the up- and down-regulation of hundreds of genes, we compared upper vs lower lobe gene expression in the small airway epithelium of the same cigarette smokers to determine if the gene expression patterns were similar or different. Active smokers (n=11) with early evidence of smoking-induced lung disease (normal spirometry but low diffusing capacity) underwent bronchoscopy and brushing of the small airway epithelium to compare upper vs lower lobe genome-wide gene expression assessed by microarray. Interestingly, cluster and principal component analysis demonstrated that, for each individual, the expression of the known small airway epithelium smoking-responsive genes were remarkably similar as upper vs lower lobe pairs, although, as expected, there were differences in the smoking-induced changes in gene expression from individual to individual. Thus, while there may be topographic differences in the distribution of cigarette smoke, sufficient smoke reaches the upper vs lower lobe small airway epithelium so that, within each smoker, the upper vs lower lobe gene expression are similar. These observations support the concept that the topographic differences in the occurrence of the smoking-induced lung diseases are likely secondary to topographic differences in the susceptibility of the upper vs lower lobes to cigarette smoke, not the topographic differences in distribution of inhaled cigarette smoke.