Targeting the untargetable KRAS in cancer therapy

Abstract

RAS is one of the most well-known proto-oncogenes. Its gain-of-function mutations occur in approximately 30% of all human cancers. As the most frequently mutated RAS isoform, KRAS is intensively studied in the past years. Despite its well-recognized importance in cancer malignancy, continuous efforts in the past three decades failed to develop approved therapies for KRAS mutant cancer. KRAS has thus long been considered to be undruggable. Encouragingly, recent studies have aroused renewed interest in the development of KRAS inhibitors either directly towards mutant KRAS or against the crucial steps required for KRAS activation. This review summarizes the most recent progress in the exploration of KRAS-targeted anticancer strategies and hopefully provides useful insights for the field.

Keywords: Cancer; Inhibitor; KRAS; Mutation; Oncogene; Targeted therapy.

Graphical abstract

Figure 1

KRAS GTPase cycle. KRAS regulation occurs through a GDP–GTP cycle that is controlled by the opposing activities of guanine nucleotide-exchange factors (GEFs), which catalyze the exchange of GDP for GTP, and GTPase-activating proteins (GAPs), which increase the rate of GTP hydrolysis to GDP. GTP bound KRAS interacts with various effector proteins, influencing the activity and/or localization of these effectors, which ultimately affects a wide spectrum of cellular pathways.

Figure 2

The major KRAS effector pathways. Oncogenic KRAS activates intracellular PI3K, MAPK or RAL-GEF pathways to promote cell survival, proliferation and cytokine secretion. Oncogenic KRAS also induces secretion of molecules that affect surrounding components of the stroma, such as fibroblasts, innate and adaptive immune cells, in a paracrine manner. These stroma cells in turn promote cancer malignancy.