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PKCα Mediates mTORC1 Activation in Non‐Small Cell Lung Carcinoma Cells with EGFR Deletion Mutation
Author(s) -
Salama Mohamed Fouda,
Liu Mengling,
Clarke Christopher,
Espaillat Mel Pilar,
Haley John,
Obeid Lina,
Hannun Yusuf
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2019.33.1_supplement.lb255
Subject(s) - cancer research , mtorc1 , epidermal growth factor receptor , protein kinase c , mutant , downregulation and upregulation , signal transduction , cell growth , biology , mutation , lung cancer , apoptosis , tyrosine kinase , microbiology and biotechnology , cancer , pi3k/akt/mtor pathway , medicine , gene , genetics
Constitutively active epidermal growth factor receptor (EGFR) mutations play critical roles in the development and progression of non‐small cell lung cancer (NSCLC). Patients with EGFR mutations are initially sensitive to EGFR‐tyrosine kinase inhibitors; however, they eventually develop drug resistance. Therefore, thorough understanding of mutant EGFR signaling is crucial in order to avoid such resistance and develop novel control therapeutic strategies. In the present study, we observed high PKCα expression in lung adenocarcinomas and in NSCLC cells with EGFR exon 19 deletion mutation. Next, we examined the role of the highly expressed PKCα in the signaling pathways downstream of mutant EGFR. Our results demonstrated that targeting PKCα either by pharmacological inhibition or downregulation impaired mTORC1 signaling, decreased proliferation, and induced caspase‐3 dependent apoptosis in cells with EGFR mutation. Moreover, PKCα gain of function was sufficient to induce proliferation of cells with wild‐type EGFR when grown under low serum conditions that was further increased when co‐expressed with mutant EGFR. Our results clearly demonstrate important roles of PKCα in regulating mTORC1 activity in NSCLC cells with mutant EGFR, whereby a switch occurs from a PKCα‐independent to a PKCα‐dependent signaling. The results suggest that PKCα could be synergistically targeted for the treatment of NSCLC with constitutively active mutant EGFR. Support or Funding Information 1. This work was supported by NCI grant CA97132 This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .