Combined inhibition of rho-associated protein kinase and EGFR suppresses the invasive phenotype in EGFR-dependent lung cancer cells

Abstract

a b s t r a c tIntroduction: Lung cancer remains the leading cause of cancer-related mortality worldwide, with metastatic disease frequently a prominent feature at the time of diagnosis. The role of NSCLC-derived EGFR mutations in cancer cell proliferation and survival has been widely reported, but little is known about the function of these mutations in invasive growth and metastasis. In this study, we sought to evaluate the intrinsic invasive properties of NSCLC cells with differing EGFR status and examine possible therapeutic targets that can abrogate invasive growth. Materials and methods: Collagen-based assays and 3D cell cultures were used to assess morphological features, actin cytoskeleton dynamics and the invasive capacity of NSCLC cell lines with differing EGFR status. The role of the RhoA/ROCK/MYPT1 and EGFR/HER pathways in NSCLC-related invasion was investigated by pharmacological inhibition and RNA interference techniques. Results: We demonstrate a positive correlation between EGFR mutational/amplification status and invasive capacity. Knockdown of wild-type and mutant EGFR leads to depletion of active and total MYPT1 levels. Combined pharmacological inhibition or genetic ablation of ROCK/EGFR suppresses the hallmarks of cancer cells and abrogates the invasive phenotype in EGFR-dependent NSCLC cells. Conclusions: These observations suggest that combined targeting of the ROCK and EGFR/HER pathways may be a potential therapeutic approach in limiting invasive growth in NSCLC.

Integrated in vivo genetic and pharmacologic screening identifies co-inhibition of EGRF and ROCK as a potential treatment regimen for triple-negative breast cancer

“…A similar pattern was seen for in vivo growth of HCC1806 cells. However, unlike the recent findings for lung cancer [54], we did not find a correlation between the response of TNBC cells to combination treatment and EGFR mutation status, phospho-EGFR, phospho-MYPT or ROCK protein levels, suggesting a cell type-specific component.…”

Impact of the APE1 Redox Function Inhibitor E3330 in Non-Small Cell Lung Cancer Cells Exposed to Cisplatin: Increased Cytotoxicity and Impairment of Cell Migration and Invasion

“…The representative cell model chosen for this purpose is the H1975 human lung adenocarcinoma cell line that was established from a non-smoker patient and possesses a mutation in the gene that confers resistance to EGFR inhibitors [40]. It is considered as a highly invasive cell line used as an adequate tool in preclinical studies towards the discovery of novel drugs for NSCLC and also in xenograft models [41].…”

The Crosstalk between Src and Hippo/YAP Signaling Pathways in Non-Small Cell Lung Cancer (NSCLC)

“…The Rho/Rho-associated protein kinase (ROCK) pathway is a downstream signaling pathway that is regulated by Src and is involved in the promotion of cancer invasion and metastasis [ 50 ]. The co-expression of Rho and Src in human NSCLC has been reported, and therapy based on the targeting of Rho/ROCK in metastatic NSCLC has been investigated in several studies [ 31 , 51 , 52 , 53 ]. Onodera et al showed that the concurrent inhibition of Src and Rho/ROCK has a synergistic effect in suppressing NSCLC cell growth [ 53 ].…”