KRAS: Biology, Inhibition, and Mechanisms of Inhibitor Resistance

Abstract

KRAS is a small GTPase that is among the most commonly mutated oncogenes in cancer. Here, we discuss KRAS biology, therapeutic avenues to target it, and mechanisms of resistance that tumors employ in response to KRAS inhibition. Several strategies are under investigation for inhibiting oncogenic KRAS, including small molecule compounds targeting specific KRAS mutations, pan-KRAS inhibitors, PROTACs, siRNAs, PNAs, and mutant KRAS-specific immunostimulatory strategies. A central challenge to therapeutic effectiveness is the frequent development of resistance to these treatments. Direct resistance mechanisms can involve KRAS mutations that reduce drug efficacy or copy number alterations that increase the expression of mutant KRAS. Indirect resistance mechanisms arise from mutations that can rescue mutant KRAS-dependent cells either by reactivating the same signaling or via alternative pathways. Further, non-mutational forms of resistance can take the form of epigenetic marks, transcriptional reprogramming, or alterations within the tumor microenvironment. As the possible strategies to inhibit KRAS expand, understanding the nuances of resistance mechanisms is paramount to the development of both enhanced therapeutics and innovative drug combinations.

Keywords: KRAS; cancer; immunotherapy; inhibitors; mutation; oncogene; resistance; targeted therapy.

Figure 1

(a) Domain architecture of KRAS; (b) frequency of KRAS mutation by disease and location. Specific amino acid changes at G12 are color-coded by relative frequency. Mutation data were downloaded from the curated set of non-redundant samples in cBioportal [1,2]. NSCLC, non-small cell lung cancer; CRC, colorectal carcinoma; PDAC, pancreatic ductal adenocarcinoma; aa, amino acid. (c) Pie charts showing the frequency of KRAS mutations in non-small cell lung cancer, colorectal cancer, and pancreatic ductal adenocarcinoma. G12 mutations are color-coded as in (b). The other category represents KRAS mutations that are not G12C, G12D, G12R, G12V, or G12S.

Figure 2

Diagram of signaling pathways related to KRAS. Growth signals stimulate KRAS to enter the active GTP-bound state. Downstream pathways, including PI3K and RAF proteins, translate active KRAS into signals for proliferation and survival. See the Glossary for acronym definitions.

Figure 3

Schematic of categories of KRAS-focused strategies for inhibiting KRAS-mutant cancers. KRAS can be inhibited at the level of DNA, mRNA, protein, or as an antigen targeting the cell for immune destruction. Inhibitor strategies are shown in red. The red star represents an activating point mutation in KRAS. On the MHC, the red star represents an antigen containing a KRAS-mutant fragment. See the Glossary for acronym definitions.

Figure 4

Model of RAS survival signals in wildtype and mutant KRAS cells. (a) In wildtype cells, KRAS, NRAS, and HRAS have overlapping functions regulating RAF activation. A pan-KRAS inhibitor may be tolerated because NRAS and HRAS can maintain normal survival signals. (b) KRAS-mutant cancer cells are rewired to be dependent on their continuous expression. The sudden inhibition of mutant KRAS rapidly decreases proliferation and survival signals, represented by red Xs. See the Glossary for acronym definitions.