Mechanisms of Resistance to KRAS Inhibitors: Cancer Cells' Strategic Use of Normal Cellular Mechanisms to Adapt

Abstract

KRAS was long deemed undruggable until the discovery of the switch-II pocket facilitated the development of specific KRAS inhibitors. Despite their introduction into clinical practice, resistance mechanisms can limit their effectiveness. Initially, tumors rely on mutant KRAS, but as they progress, they may shift to alternative pathways, resulting in intrinsic resistance. This resistance can stem from mechanisms like epithelial-to-mesenchymal transition (EMT), YAP activation, or KEAP1 mutations. KRAS inhibition often triggers cellular rewiring to counteract therapeutic pressure. For instance, feedback reactivation of signaling pathways such as MAPK, mediated by receptor tyrosine kinases, supports tumor cell survival. Inhibiting KRAS disrupts protein homeostasis, but reactivation of MAPK or AKT can restore it, aiding tumor cell survival. KRAS inhibition also causes metabolic reprogramming and protein re-localization. The re-localization of E-cadherin and Scribble from the membrane to the cytosol causes YAP to translocate to the nucleus, where it drives MRAS transcription, leading to MAPK reactivation. Emerging evidence indicates that changes in cell identity, such as mucinous differentiation, shifts from alveolar type 2 to type 1 cells, or lineage switching from adenocarcinoma to squamous cell carcinoma, also contribute to resistance. In addition to these nongenetic mechanisms, secondary mutations in KRAS or alterations in upstream/downstream signaling proteins can cause acquired resistance. Secondary mutations in the switch-II pocket disrupt drug binding, and known oncogenic mutations affect drug efficacy. Overcoming these resistance mechanisms involves enhancing the efficacy of drugs targeting mutant KRAS, developing broad-spectrum inhibitors, combining therapies targeting multiple pathways, and integrating immune checkpoint inhibitors.

Keywords: KRAS; lineage plasticity; nongenetic mechanism; resistance; secondary mutation.

FIGURE 1

Distribution of KRAS mutations across different cancer types and variants. (A) KRAS mutation frequency across 32 TCGA cancer types. The data were generated using cBioPortal (https://www.cbioportal.org). (B) Pie charts illustrating the frequencies of different KRAS mutations in KRAS‐mutated lung, colorectal, pancreatic, and endometrial cancers. Each cancer type exhibits a distinct ‘KRAS profile’.

FIGURE 2

Types and modalities of RAS inhibitors.

FIGURE 3

Representative resistance mechanisms to KRAS inhibitors. (A) Intrinsic resistance mechanisms: While mutant KRAS is essential for tumorigenesis, tumor cells can acquire KRAS independence during proliferation through processes such as epithelial–mesenchymal transition (EMT), YAP activation, or metabolic reprogramming. As a result, these tumor cells become insensitive to KRAS inhibitors. (B) Adaptive resistance mechanisms: Inhibition of mutant KRAS leads to feedback reactivation of receptor tyrosine kinases (RTKs), which in turn reactivates downstream signaling pathways or reconstitutes protein homeostasis. Tumor cells can also adapt to KRAS inhibitors by altering cell identity or inducing protein re‐localization, resulting in YAP nuclear translocation and activation of YAP‐mediated signaling. (C) Acquired resistance mechanisms: Acquired resistance is mediated by secondary mutations in the target protein, activation of alternative pathways through other receptors or downstream proteins, or phenotypic transformation. The first two categories are primarily driven by genetic mechanisms, while the third represents a non‐genetic mechanism of resistance.

FIGURE 4

Role of protein localization in the development of resistance to KRAS inhibitors. (A) In the absence of the drug, mutant KRAS activates MAPK signaling, which facilitates the membrane localization of Scribble (Scrib). Scribble then forms a complex with SHOC2/PP1c, inhibiting the nuclear translocation of YAP. (B) Inhibition of KRAS G12C reduces MAPK activation, leading to decreased membrane localization of Scribble. Consequently, Scribble is unable to inhibit YAP, allowing YAP to translocate to the nucleus and promote the transcription of its downstream targets, including MRAS. (C) MRAS moves to the membrane, where it is activated by RTKs. The GTP‐bound MRAS then forms a complex with SHOC2/PP1a, which dephosphorylates CRAF, resulting in the reactivation of MAPK signaling.

FIGURE 5

Role of lineage plasticity in the development of resistance to KRAS inhibitors in KRAS mutant lung cancer. Lung adenocarcinoma predominantly originates from alveolar type 2 (AT2) epithelial cells, which act as facultative alveolar stem cells by self‐renewing and replacing alveolar type 1 (AT1) cells. KRAS inhibition promotes a transition to mucinous histological features, a quiescent AT1‐like cancer cell state, a mesenchymal‐like cell phenotype, and a squamous cell lung cancer phenotype, which collectively contribute to resistance to KRAS inhibitors. For mucinous and/or AT1 differentiation, tumor cells enter a drug‐tolerant persister state, serving as a reservoir for full resistance driven by other mechanisms, such as secondary mutations. The adeno‐squamous transition is driven by epigenetic and transcriptional changes including ELF5 and VEZF1, which appear to be further enhanced by LKB1 mutations.