Drugging the undruggable RAS: Mission Possible?

Abstract

Despite more than three decades of intensive effort, no effective pharmacologic inhibitors of the Ras oncoproteins have reached the clinic, prompting the widely held perception that Ras proteins are “undruggable”. However, there is renewed hope that this is not the case. In this review, we summarize the progress and promise of five key directions. First, we focus on the prospects of direct inhibitors of Ras. Second, we revisit the issue of whether blocking Ras membrane association is a viable approach. Third, we assess the status of targeting Ras downstream effector signalling, arguably the most favourable current direction. Fourth, we address whether the search for synthetic lethal interactors of mutant RAS still holds promise. Finally, Ras-mediated changes in cell metabolism have recently been described. Can these changes be exploited for new therapeutic directions? We conclude with perspectives on how additional complexities, not yet fully understood, may impact each of these approaches.

WOMEN IN CANCER THEMATIC REVIEW: Systemic therapies in neuroendocrine tumors and novel approaches toward personalized medicine

“…Three publications reported low-frequency KRAS mutations (10-20%) also in pNET (Yuan et al 2014, Vijayvergia et al 2016, Kimura et al 2016. Although targeting RAS directly is a mission impossible (Cox et al 2014), new options arouse from targeting RAS downstream effectors and cell cycle checkpoint control. In NRAS mutant melanomas (Ascierto et al 2016), inhibition of MEK produced a partial response in a subset of patients.…”

Farnesyl transferase inhibitor FTI-277 inhibits breast cell invasion and migration by blocking H-Ras activation

“…However, these drugs failed to increase survival in clinical trials of patients with K-Ras mutated pancreatic cancer (12). N-Ras and K-Ras become substrates for geranylgeranyltransferase I, resulting in alternative prenylation and membrane targeting (9,13). By contrast, H-Ras has no alternative prenylation for membrane targeting.…”

Selective targeting of point-mutated KRAS through artificial microRNAs

“…KRAS targeting represents a particularly important opportunity for impacting cancer therapy, given that KRAS mutations are involved in the development of several types of cancers (3). Attempts at targeting point-mutated KRAS have consisted of siRNAs directly targeting this oncogene and associated pathways.…”

“…Specifically, Kras, a GTPase protein, is frequently mutated in codon 12 of its coding sequence (CDS) in large fractions of specific human cancer types (2,3). For example, the G12S mutation, in which a single nucleotide modification leads to the substitution of a glycine (Gly) for a serine (Ser), confers constitutive activation of KRAS, inducing cell proliferation (4)(5)(6).…”