Synthetic Vulnerabilities in the KRAS Pathway

Abstract

Mutations in Kristen Rat Sarcoma viral oncogene (KRAS) are among the most frequent gain-of-function genetic alterations in human cancer. Most KRAS-driven cancers depend on its sustained expression and signaling. Despite spectacular recent success in the development of inhibitors targeting specific KRAS alleles, the discovery and utilization of effective directed therapies for KRAS-mutant cancers remains a major unmet need. One potential approach is the identification of KRAS-specific synthetic lethal vulnerabilities. For example, while KRAS-driven oncogenesis requires the activation of a number of signaling pathways, it also triggers stress response pathways in cancer cells that could potentially be targeted for therapeutic benefit. This review will discuss how the latest advances in functional genomics and the development of more refined models have demonstrated the existence of molecular pathways that can be exploited to uncover synthetic lethal interactions with a promising future as potential clinical treatments in KRAS-mutant cancers.

Keywords: KRAS; cancer; synthetic lethality.

Figure 1

KRAS downstream effector pathways. The active form of KRAS (KRAS-GTP) regulates many signaling pathways affecting essential cellular functions such as cell proliferation, migration, survival, differentiation, endocytosis, migration and angiogenesis through the interaction with different effectors. Adapted from Soriano et al. [52]. Further detail regarding therapeutic approaches is provided in Table 1. Figure made in https://biorender.com (accessed on 31 May 2022).

Figure 2

Synthetic lethality as a therapeutic strategy in cancers driven by oncogenes. Synthetic lethality happens when the alteration of an oncogene or gene X in isolation is compatible with cellular viability, whereas loss of both genes together leads to cellular lethality. Cancer-driving genetic alterations are commonly associated with dependencies that are specific to these alterations and absent in normal non-neoplastic cells. The presence of one of these dependencies in cancer cells but not in normal cells can therefore create opportunities to selectively kill cancer cells by mimicking the effect of the second genetic mutation with targeted therapy. Figure made in https://biorender.com (accessed on 31 May 2022).