PKCα is required for Akt-mTORC1 activation in non-small cell lung carcinoma (NSCLC) with EGFR mutation

Abstract

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.

PRKCA Overexpression Is Frequent in Young Oral Tongue Squamous Cell Carcinoma Patients and Is Associated with Poor Prognosis

“…The role of PRKCA as a tumorigenic marker is plausible: Protein kinase C isoforms have been long identified as the intracellular receptors of phorbol esters that promote tumor formation during two-stage chemical-induced carcinogenesis in mouse skin [ 36 , 37 ]. Subsequently, PRKCA has been shown to intersect with the MAPK/ERK and PI3K/AKT pathways, which are frequently active in several cancer types, promoting tumor progression by suppressing apoptosis and inducing proliferation, migration, invasion and angiogenesis [ 38 , 39 , 40 , 41 , 42 , 43 , 44 ].…”

“…patients in recent decades could suggest a role of environmental, dietary or lifestyle factors, though alcohol, smoking and HPV do not play a substantial role. [40][41][42][43][44]. Both pathways are known to promote cell growth, proliferation, migration and invasion.…”

“…The occurrence of distinct early-onset OTSCC subtypes and varying subtype distributions in study cohorts would offer a possible explanation for controversial reports about survival in young OTSCC patients. [40][41][42][43][44]. Both pathways are known to promote cell growth, proliferation, migration and invasion.…”

“… Model of the role of PRKCA in tumorigenesis and progression. Activation of PRKCA is known to elicit downstream tumor-promoting effects via the MAPK/Erk and PI3K/Akt signaling pathways in several cancer types [ 40 , 41 , 42 , 43 , 44 ]. Both pathways are known to promote cell growth, proliferation, migration and invasion.…”

Protein Kinase C as a Therapeutic Target in Non-Small Cell Lung Cancer

“…Clinically, PKCδ upregulation correlated negatively with OS in TKI-treated Δ EGFR NSCLC patients [ 84 ]. Interestingly, our recently published work has demonstrated that there is a Δ EGFR -independent selection for high PKCα protein expression in NSCLC, and a Δ EGFR -dependent activation of PKCα that translates to constitutive downstream signaling to AKT/mTOR pathway [ 113 ]. In BRAF / KRAS mutant NSCLC, PKCα was shown to modulate sensitivity to chemotherapy via mediating MDR1 expression and RLIP76 phosphorylation ( Figure 4 ) [ 40 , 41 , 42 ].…”