Targeting PKCι-PAK1 signaling pathways in EGFR and KRAS mutant adenocarcinoma and lung squamous cell carcinoma

Ito, Masaoki; Codony-Servat, Carles; Codony-Servat, Jordi; Lligé, David; Chaib, Imane; Sun, Xiaoyan; Jing, Miao; Sun, Rongwei; Cai, Xueting; Verlicchi, Alberto; Okada, Morihito; Molina-Vila, Miguel Ángel; Karachaliou, Niki; Cao, Peng; Rosell, Rafael

doi:10.1186/s12964-019-0446-z

Cited by 23 publications

(17 citation statements)

References 49 publications

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“…7,8 KRAS mutations correlate significantly to poor therapeutic response in NSCLC patients. [9][10][11] Therefore, it is essential to develop novel KRAS-targeting drugs for treating recalcitrant NSCLC patients with KRAS mutations.…”

Section: Introductionmentioning

confidence: 99%

<p>Anlotinib Exerts Anti-Cancer Effects on KRAS-Mutated Lung Cancer Cell Through Suppressing the MEK/ERK Pathway</p>

Liu

Tan

et al. 2020

CMAR

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Background: With a high frequency of 30%, KRAS mutations in patients with non-small cell lung cancer (NSCLC) often lead to their poor response to most anti-cancer therapies. As a multi-target tyrosine kinase inhibitor, Anlotinib shows clinical efficacy against several types of cancer. However, its effects on KRAS mutant NSCLC and the underlying molecular mechanisms remain unclear. Materials and Methods: Cell counting Kit-8 assay, colony formation assay, flow cytometry analysis, wound healing scratch assay, Transwell assay and xenograft mouse model were used to evaluate the anti-cancer effects of Anlotinib. The potential molecular mechanisms were determined by immunohistochemistry (IHC) and Western blotting. Results: Anlotinib inhibited proliferation of KRAS mutant lung cancer cells and induced apoptosis in vitro. In addition, the migration and invasion abilities of these cells were also decreased after treatment with Anlotinib. It significantly suppressed tumor growth in vivo and prolonged the survival of the xenograft-bearing mice, which correlated to lower expression levels of Ki67 in the tumor tissues. Mechanistically, Anlotinib downregulated MEK and ERK as well as their phosphorylated forms in the KRAS mutant lung cancer cells. Conclusion: Anlotinib inhibits the growth of KRAS mutant lung cancer cells partly via the suppression of the MEK/ERK pathway. Our findings provide novel insights into treating recalcitrant KRAS mutated NSCLC.

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Section: Introductionmentioning

confidence: 99%

<p>Anlotinib Exerts Anti-Cancer Effects on KRAS-Mutated Lung Cancer Cell Through Suppressing the MEK/ERK Pathway</p>

Liu

Tan

et al. 2020

CMAR

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“…However, patients treated with EGFR tyrosine kinase inhibitors usually acquire resistance after 9-12 months. Previous studies on EGFR mutations showed that a PAK1 inhibitor, administered in combination with a selective inhibitor of protein kinase C, was effective against the acquisition of resistance induced by EGFR tyrosine kinase inhibitors [28,29]. We found that the five-year mortality rates were lower in patients with PAK1-negative than in PAK1-positive EGFR mutant lung cancer.…”

Section: Discussionmentioning

confidence: 56%

PAK1 as a Potential Therapeutic Target in Male Smokers with EGFR-Mutant Non-Small Cell Lung Cancer

et al. 2020

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P21-activated kinases (PAKs) are serine/threonine protein kinases that contribute to several cellular processes. Here, we aimed to determine the prognostic value of PAK1 and its correlation with the clinicopathological characteristics and five-year survival rates in patients with non-small cell lung cancer (NSCLC). We evaluated PAK1 mRNA and protein expression in NSCLC cells and resected tumor specimens, as well as in healthy human bronchial epithelial cells and adjacent healthy lung tissues, respectively, for effective comparison. Immunohistochemical tissue microarray analysis of 201 NSCLC specimens showed the correlation of PAK1 expression with clinicopathological characteristics. The mRNA and protein expression of PAK1 were 2.9- and 4.3-fold higher in six of seven NSCLC cell types and human tumors (both, p < 0.001) than in healthy human bronchial epithelial BEAS-2B cells and adjacent healthy lung tissues, respectively. Decreased survival was significantly associated with PAK1 overexpression in the entire cohort (χ2 = 8.48, p = 0.0036), men (χ2 = 17.1, p < 0.0001), and current and former smokers (χ2 = 19.2, p < 0.0001). Notably, epidermal growth factor receptor (EGFR) mutation-positive lung cancer patients with high PAK1 expression showed higher mortality rates than those with low PAK1 expression (91.3% vs. 62.5%, p = 0.02). Therefore, PAK1 overexpression could serve as a molecular target for the treatment of EGFR mutation-positive lung cancer, especially among male patients and current/former smokers.

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“…Since it has been proven that OTSSP167 does not selectively inhibit MELK [49,50], we cannot exclude that part of the anti-growth function (s) of OTSSP167 is due to off-target effects of the drug. In support of the latter hypothesis, a recent investigation showed that OTSSP167 hampers the proliferation and colony formation ability of lung cancer cell lines, as well as carcinogenesis in lung cancer xenografts via the suppression of the PAK1 protooncogene [52]. Furthermore, it has been found that MELK suppression by siRNA did not recapitulate the mitotic effects of OTSSP167 treatment in MCF7 and Hela cancer cell lines.…”

Section: Discussionmentioning

confidence: 97%

Inhibition of MELK Protooncogene as an Innovative Treatment for Intrahepatic Cholangiocarcinoma

et al. 2019

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Background and Objectives: Intrahepatic cholangiocarcinoma (iCCA) is a pernicious tumor characterized by a dismal outcome and scarce therapeutic options. To substantially improve the prognosis of iCCA patients, a better understanding of the molecular mechanisms responsible for development and progression of this disease is imperative. In the present study, we aimed at elucidating the role of the maternal embryonic leucine zipper kinase (MELK) protooncogene in iCCA. Materials and Methods: We analyzed the expression of MELK and two putative targets, Forkhead Box M1 (FOXM1) and Enhancer of Zeste Homolog 2 (EZH2), in a collection of human iCCA by real-time RT-PCR and immunohistochemistry (IHC). The effects on iCCA growth of both the multi-kinase inhibitor OTSSP167 and specific small-interfering RNA (siRNA) against MELK were investigated in iCCA cell lines. Results: Expression of MELK was significantly higher in tumors than in corresponding non-neoplastic liver counterparts, with highest levels of MELK being associated with patients’ shorter survival length. In vitro, OTSSP167 suppressed the growth of iCCA cell lines in a dose-dependent manner by reducing proliferation and inducing apoptosis. These effects were amplified when OTSSP167 administration was coupled to the DNA-damaging agent doxorubicin. Similar results, but less remarkable, were obtained when MELK was silenced by specific siRNA in the same cells. At the molecular level, siRNA against MELK triggered downregulation of MELK and its targets. Finally, we found that MELK is a downstream target of the E2F1 transcription factor. Conclusion: Our results indicate that MELK is ubiquitously overexpressed in iCCA, where it may represent a prognostic indicator and a therapeutic target. In particular, the combination of OTSSP167 (or other, more specific MELK inhibitors) with DNA-damaging agents might be a potentially effective therapy for human iCCA.

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Targeting PKCι-PAK1 signaling pathways in EGFR and KRAS mutant adenocarcinoma and lung squamous cell carcinoma

Cited by 23 publications

References 49 publications

<p>Anlotinib Exerts Anti-Cancer Effects on KRAS-Mutated Lung Cancer Cell Through Suppressing the MEK/ERK Pathway</p>

<p>Anlotinib Exerts Anti-Cancer Effects on KRAS-Mutated Lung Cancer Cell Through Suppressing the MEK/ERK Pathway</p>

PAK1 as a Potential Therapeutic Target in Male Smokers with EGFR-Mutant Non-Small Cell Lung Cancer

Inhibition of MELK Protooncogene as an Innovative Treatment for Intrahepatic Cholangiocarcinoma

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