Targeting KRAS mutations: orchestrating cancer evolution and therapeutic challenges

Abstract

Activating KRAS mutations are highly relevant to various cancers, and KRAS is the most frequently altered oncogenic protein in solid tumors. While historically considered undruggable, two KRAS^G12C inactive state-selective inhibitors are currently approved for treating patients with non-small cell lung cancer. However, these agents only demonstrate a 30-40% response rate and a median progression-free survival of approximately 6 months, with the inevitable emergence of resistance mechanisms, hence remaining far from achieving a cure. Additionally, several cancers with poor prognostic outcomes, such as pancreatic adenocarcinoma, are driven by other non-G12C KRAS mutations and thus have no effective targeted therapies. Improvements in understanding RAS signaling, RNA, and nucleic acid chemistry, as well as the role of the tumor microenvironment, have sparked a paradigm shift in the approach to KRAS inhibition and suggested the potential for several novel combination therapies. In this review, we provide an overview of the RAS pathway and discuss the ongoing development and status of therapeutic strategies for targeting the oncogenic RAS. We further delve into the challenges of resistance mechanisms to better understand the rationale behind these developing strategies, describe their mechanisms of action, and offer insights into the current clinical trial status of each of these approaches.

Fig. 1

The KRAS signaling pathway and downstream effectors. The binding of epidermal (EGF) and platelet-derived (PDGF) growth factors to transmembrane receptors activates the intracellular phosphorylation (P) of inactive guanine diphosphate (GDP)-bound KRAS to its active triphosphate (GTP) form via guanine-exchange factor (GEF). Active wild-type KRAS subsequently activates downstream signaling pathways, including the RAS/MEK/ERK and PI3K/AKT/mTOR pathways, among others, thus leading to increased survival, proliferation, migration, differentiation, and invasion. Created in BioRender.com

Fig. 2

Prevalence of KRAS mutations. a Describes the prevalence (%) of the different types of KRAS mutations and alterations across all tumor types. b Further describes the frequency (%) of G12 mutations in comparison to other non-G12 KRAS mutations and alterations. c depicts the prevalence (y-axis-%) of specific KRAS mutations (x-axis) in non-small cell lung cancer (NSCLC), colorectal cancer, and pancreatic cancer. Created in BioRender.com

Fig. 3

Historical timeline of major milestones in KRAS discovery and therapeutic development (1973–2025). This timeline charts the evolution of KRAS research from its identification in the Kristen rat sarcoma virus to the advent of next-generation therapies. Early decades defined KRAS biology and its role as a crucial oncogenic driver. The 2010 era marked a paradigm shift with the emergence of direct KRASG12C inhibitors, followed by diversification of targeting strategies into nucleic acid therapeutics, PROTACs, and immunotherapies. Current efforts focus on multimodal and next-generation strategies aimed at overcoming resistance and expanding therapeutic reach. Created in BioRender.com

Fig. 4

Resistance mechanisms and therapeutic strategies. Resistance mechanisms to KRAS inhibition are classified as putative genetic (point mutations; red) or nongenetic (bypass pathways; blue). a Represents the prevalence of each type of resistance mechanism in non-small cell lung cancer (NSCLC), colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), and other gastrointestinal (GI) malignancies. b Represents potential therapeutic strategies to circumvent resistance to KRAS inhibitors, including inhibitors of genetic mechanisms (light pink) and inhibitors of bypass pathways (light blue). c Represents histological transformation through epithelial‒mesenchymal transition (EMT) as a mechanism of resistance to KRAS inhibition. Created in BioRender.com

Fig. 5

Mechanism of KRAS-On-State Targeting. KRAS-on-state inhibitors are classified into mutation-specific inhibitors (target mutations individually; blue panel), pan-KRAS inhibitors (targeting KRAS irrespective of mutations; beige panel), and pan-RAS inhibitors (targeting KRAS, NRAS, and HRAS; light green panel) (a). On-state targeting includes the binding of the inhibitor to cyclophilin to form a bicomplex, which in turn binds to KRAS in its active-GTP form, resulting in the inhibition of the Tri-complex KRAS (b). Created in BioRender.com

Fig. 6

Summary of KRAS-targeting strategies. This figure summarizes different KRAS-targeting strategies beyond the currently approved small-molecule inhibitors (pink). Strategies include combination approaches with KRAS inhibitors (light blue), RAS-ON inhibition (yellow), the use of PRTOAC (purple), and nucleic acid-based therapies (gray), such as mRNA vaccines, siRNAs, and CRISPR‒Cas-based therapies. TCR T-cell receptor, pMHC peptide-major histocompatibility complex. Created in BioRender.com