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Targeting PKC?-PAK1 in EGFR-mutation positive non-small cell lung cancer.

ABSTRACT: Background:Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) induce significant responses in EGFR-mutation positive non-small cell lung cancer (NSCLC). However, universal progression is observed. Methods:The effect of the anti-rheumatoid agent, auranofin, a selective inhibitor of oncogenic protein kinase C iota (PKC?) signaling and IPA-3, a non-ATP competitive p21-activated kinase 1 (PAK1) inhibitor in treatment-naïve and EGFR TKI-resistant EGFR-mutation positive NSCLC cell lines was investigated. PC9 and HCC827 cells were used. The four EGFR-TKI resistant cell lines were established from PC9. Cell viability assays, drug combination studies, and western blotting were performed. The combination index, and RTK or non-RTK expression were performed. Results:The combination of IPA-3 and auranofin was highly synergistic in all 6 cell lines (combination indexes ranged from 0.37-0.62). The activities on EGFR, CDCP1, AXL, MET, and downstream effector pathways, including PAK1, PKC?, ERK, AKT, STAT3, Src, and YAP1 were abrogated. Conclusions:The combination of auranofin with IPA-3 could be a potential therapy for EGFR-mutation positive NSCLC resistant to EGFR TKIs. Auranofin with IPA-3 could become a therapeutic solution for EGFR-mutation positive NSCLC patients resistant to EGFR TKIs.

SUBMITTER: Ito M

PROVIDER: S-EPMC6835115 | biostudies-literature | 2019 Oct

REPOSITORIES: biostudies-literature

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Targeting PKCι-PAK1 in EGFR-mutation positive non-small cell lung cancer.

Ito Masaoki M Codony-Servat Carles C Karachaliou Niki N Rosell Rafael R

Translational lung cancer research 20191001 5

<h4>Background</h4>Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) induce significant responses in EGFR-mutation positive non-small cell lung cancer (NSCLC). However, universal progression is observed.<h4>Methods</h4>The effect of the anti-rheumatoid agent, auranofin, a selective inhibitor of oncogenic protein kinase C iota (PKCι) signaling and IPA-3, a non-ATP competitive p21-activated kinase 1 (PAK1) inhibitor in treatment-naïve and EGFR TKI-resistant EGFR-mutation po ...[more]

PMID: 31737502

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Project description:Mutational activation of the epidermal growth factor receptor (EGFR) is a major player in the pathogenesis of non-small cell lung cancer (NSCLC). NSCLC patients with constitutively active EGFR mutations eventually develop drug resistance against EGFR tyrosine-kinase inhibitors; therefore, better understandings of key components of mutant EGFR (mtEGFR) signaling are required. Here, we initially observed aberrantly high expression of protein kinase C? (PKC?) in lung adenocarcinomas, especially those with EGFR mutations, and proceeded to examine the role of PKC? in the regulation of the signaling pathways downstream of mtEGFR. The results showed that NSCLC cell lines with constitutively active EGFR mutations tend to have very or moderately high PKC? levels. Furthermore, PKC? was constitutively activated in HCC827 and H4006 cells which have an EGFR deletion mutation in exon 19. Interestingly, mtEGFR was not required for the induction of PKC? at protein and message levels suggesting that the increased levels of PKC? are due to independent selection. On the other hand, mtEGFR activity was required for robust activation of PKC?. Loss of functions studies revealed that the NSCLC cells rely heavily on PKC? for the activation of the mTORC1 signaling pathway. Unexpectedly, the results demonstrated that PKC? was required for activation of Akt upstream of mTOR but only in cells with the mtEGFR and with the increased expression of PKC?. Functionally, inhibition of PKC? in HCC827 led to caspase-3-dependent apoptosis and a significant decrease in cell survival in response to cellular stress induced by serum starvation. In summary, the results identified important roles of PKC? in regulating mTORC1 activity in lung cancer cells, whereby a primary switching occurs from PKC?-independent to PKC?-dependent signaling in the presence of EGFR mutations. The results present PKC? as a potential synergistic target of personalized treatment for NSCLC with constitutively active mutant forms of EGFR and constitutively active PKC?.

Dataset Information

Targeting PKC?-PAK1 in EGFR-mutation positive non-small cell lung cancer.

Publications

Targeting PKCι-PAK1 in EGFR-mutation positive non-small cell lung cancer.

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