Abstract
Introductionp21-activated kinase 1 (PAK1) stimulates growth and metastasis in non-small cell lung cancer (NSCLC). Protein kinase C iota (PKCι) is an enzyme highly expressed in NSCLC, regulating PAK1 signaling. In the present study we explored whether the PKCι-PAK1 signaling pathway approach can be an efficient target in different types of NSCLC cell and mouse models.MethodsThe effect of IPA-3 (PAK1 inhibitor) plus auranofin (PKCι inhibitor) combination was evaluated by cell viability assay, colony formation and western blotting assay, using three types of NSCLC cell lines: EGFR or KRAS mutant adenocarcinoma and squamous cell carcinoma with PAK1 amplification. In addition, for clinical availability, screening for new PAK1 inhibitors was carried out and the compound OTSSP167 was evaluated in combination with auranofin in cell and mice models.ResultsThe combination of IPA-3 or OTSSP167 plus auranofin showed high synergism for inhibiting cell viability and colony formation in three cell lines. Mechanistic characterization revealed that this drug combination abrogated expression and activation of membrane receptors and downstream signaling proteins crucial in lung cancer: EGFR, MET, PAK1, PKCι, ERK1/2, AKT, YAP1 and mTOR. A nude mouse xenograft assay demonstrated that this drug combination strongly suppressed tumor volume compared with single drug treatment.ConclusionsCombination of IPA-3 or OTSSP167 and auranofin was highly synergistic in EGFR or KRAS mutant adenocarcinoma and squamous cell carcinoma cell lines and decreased tumor volume in mice models. It is of interest to further test the targeting of PKCι-PAK1 signaling pathways in EGFR mutant, KRAS mutant and squamous NSCLC patients.
Highlights
Non-small cell lung cancer (NSCLC) is the leading cause of cancer related deaths and comprises several histological subtypes: lung adenocarcinoma (LUAD), squamous cell carcinoma (SCC) and large cell carcinoma
We focus our research on the identification of recurrent pathways occurring in subclasses of NSCLC, including LUADs driven by KRAS or ERK 1/2 (EGFR) mutations, and SCC
The combination of a p21-activated kinase 1 (PAK1) inhibitor plus antitumoral compounds showed cell viability and colony formation inhibition synergy To investigate the potential antitumoral properties and possible synergistic effect of a PAK inhibitor (IPA-3) combination with several compounds used in cancer treatment, such as EGFR inhibitors, PKCι inhibitor, MEK inhibitor, and a Flk3/Syk, and potential multiple PKC inhibitor, several lung cancer cell lines possessing different molecular characteristics were tested, such as HCC827 (EGFR mutated), H23 (KRAS mutated) and H520 (PAK1 overexpression)
Summary
Non-small cell lung cancer (NSCLC) is the leading cause of cancer related deaths and comprises several histological subtypes: lung adenocarcinoma (LUAD), squamous cell carcinoma (SCC) and large cell carcinoma. PKCι mRNA is overexpressed in LUAD and SCC cell lines and tumor tissue, and is predictive of poor outcome [12]. We posit that different classes of LUADs, such as EGFR mutant LUADs, KRAS mutant LUADs and SCCs, could be sensitive to the inhibition of PKCι with auranofin plus a PAK inhibitor. Several attempts have been made to target PAK1 in cancer, its catalytic pocket is large and highly flexible, in addition to its highly mobile N-terminal lobe, which presented a challenge in preventing specific PAK inhibitors [24, 25] For this reason, we used IPA-3 (2,2′-dihydroxy-1,1′-dinaphthyldisulfide) as a PAK inhibitor [26] with PKCι inhibitor
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