Is Ras a potential target in treatment against cutaneous squamous cell carcinoma?

Hyperactive retrovirus-associated DNA sequence (Ras) genes have been found in human cancers and are involved in cancer pathogenesis. Salirasib, one anti-Ras compound, was reported to exhibit antitumoral effects, but its role remains unclear in cutaneous squamous cell carcinoma (cSCC). In our study, salirasib treatment led to deregulation of c-Raf, ERK and Akt signaling, blockage of MTOR signaling, interruption on Beclin 1-related autophagy regulation, activation of apoptosis and down-regulation of some cell cycle regulatory proteins in primary human epidermal keratinocyte (HEK)s, but did not exhibit similar effects in the human cSCC cell line COLO-16. MEK inhibitor U0126 can lead to dephosphorylation of MTOR and Rictor in COLO-16 cells; however, c-Raf was not yet down-regulated after salirasib treatment in the presence of U0126. Furthermore, we verified that the Ras activity could be suppressed by salirasib, and there was no loss-of-function mutation in c-Raf in HEKs and COLO-16 cells. In summary, salirasib does not exhibit antitumoral effects in the cSCC cells in assays in vitro. We speculated that the disability of signaling transmission from Ras to c-Raf in COLO-16 cells might contribute to the ineffective performance of salirasib.