Synthetic Lethal Vulnerabilities in KRAS-Mutant Cancers

Abstract

KRAS is the most commonly mutated oncogene in human cancer. Most KRAS-mutant cancers depend on sustained expression and signaling of KRAS, thus making it a high-priority therapeutic target. Unfortunately, development of direct small molecule inhibitors of KRAS function has been challenging. An alternative therapeutic strategy for KRAS-mutant malignancies involves targeting codependent vulnerabilities or synthetic lethal partners that are preferentially essential in the setting of oncogenic KRAS. KRAS activates numerous effector pathways that mediate proliferation and survival signals. Moreover, cancer cells must cope with substantial oncogenic stress conferred by mutant KRAS. These oncogenic signaling pathways and compensatory coping mechanisms of KRAS-mutant cancer cells form the basis for synthetic lethal interactions. Here, we review the compendium of previously identified codependencies in KRAS-mutant cancers, including the results of numerous functional genetic screens aimed at identifying KRAS synthetic lethal targets. Importantly, many of these vulnerabilities may represent tractable therapeutic opportunities.

Figure 1.

Synthetic lethality as a therapeutic paradigm in cancer. (A) In normal healthy cells, wild-type (WT) KRAS is activated by appropriate mitogenic stimuli such as receptor tyrosine kinase–mediated growth factor signaling. (B) In cancer cells with KRAS mutation, aberrant effector signaling mediates oncogenic proliferation and survival but also creates oncogenic stress to which cancer cells must adapt to sustain oncogenic growth. These downstream aberrant effector signaling pathways as well as parallel adaptive pathways that mitigate oncogenic stress represent unique features of KRAS-mutant cells that may include selective vulnerabilities and synthetic lethal targets. (C) Synthetic lethal targets refer to those targets whose inhibition results in cell death only in the presence of another mutation (i.e., KRAS mutation). Broadly applied, this concept may represent targets that act (1) downstream of aberrant effector signaling, or (2) in parallel adaptive pathways. In theory, synthetic lethal therapies result in cell death of the KRAS-mutant cancer cells, but not in normal cells (shown in A) because the aberrant oncogenic signals or parallel adaptive processes are not present in these KRAS WT cells.

Figure 2.

KRAS oncogenic stress and adaptation.