KRAS mutation: from undruggable to druggable in cancer

Abstract

Cancer is the leading cause of death worldwide, and its treatment and outcomes have been dramatically revolutionised by targeted therapies. As the most frequently mutated oncogene, Kirsten rat sarcoma viral oncogene homologue (KRAS) has attracted substantial attention. The understanding of KRAS is constantly being updated by numerous studies on KRAS in the initiation and progression of cancer diseases. However, KRAS has been deemed a challenging therapeutic target, even "undruggable", after drug-targeting efforts over the past four decades. Recently, there have been surprising advances in directly targeted drugs for KRAS, especially in KRAS (G12C) inhibitors, such as AMG510 (sotorasib) and MRTX849 (adagrasib), which have obtained encouraging results in clinical trials. Excitingly, AMG510 was the first drug-targeting KRAS (G12C) to be approved for clinical use this year. This review summarises the most recent understanding of fundamental aspects of KRAS, the relationship between the KRAS mutations and tumour immune evasion, and new progress in targeting KRAS, particularly KRAS (G12C). Moreover, the possible mechanisms of resistance to KRAS (G12C) inhibitors and possible combination therapies are summarised, with a view to providing the best regimen for individualised treatment with KRAS (G12C) inhibitors and achieving truly precise treatment.

Fig. 1

The structure and function of KRAS. a According to homology, KRAS, which consists of 188/189 amino acids can be divided into three parts. The first part consisting of the first 85 amino acid residues is a highly conserved region. The next 80 amino acid residues are defined as a second part where homology between any pair of human RAS genes is 85%. A third part is a highly variable region and homology is only 8%. KRAS forms two major domains: a catalytic domain called the G domain and a hypervariable region (HVR). The G domain consists of three regions: switch I, switch II and the P loop, which binds guanine nucleotides and activates signalling pathway by interacting with effectors. The HVR consists of a membrane-targeting domain containing the CAAX motif where C is a cysteine, A is any aliphatic amino acid and X is any amide acid, which acquires lipids by farnesyl or prenyl modification. b The normal function of KRAS depends on the membrane localisation of its post-transcriptional modification, which is mediated by a series of enzymes. KRAS functions as a guanosine diphosphate (GDP)/triphosphate (GTP) binary switch, which controls important signal transduction from activated membrane receptors to intracellular molecules. The binary switch is mainly determined by two kinds of regulatory proteins: guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). FTase: farnesyltransferase; GGTase: geranyl geranyltransferase; RCE1: RAS-converting enzyme 1; ICMT: isoprenylcysteine carboxyl methyltransferase; PDEδ: phosphodiesterase δ

Fig. 2

The regulation of KRAS activation and signal transduction. The canonical and well-known pattern of activating KRAS is dependent on correct membrane localisation and adjacent activation of membrane receptors. In the resting state, KRAS normally binds with GDP in an inactivated state. When the extracellular growth factors such as EGF transmit signals to receptors, the SOS, a kind of GEF, interacts with the KRAS-GDP complex leading to the release of GDP and the replacement of GTP. The tether of GTP and KRAS induces structural changes of switch I and switch II, thereby activating KRAS. In contrast, GAPs enhance intrinsic GTPase activity in KRAS to accelerate the reaction in which GTP is hydrolysed to GDP. The KRAS cycle between the activated and inactivated conformations functions as a finely regulated molecular switch that controls multiple signalling cascades, including the canonical RAF-MEK-ERK pathway, which controls proliferation; PI3K-AKT-mTOR pathway, which promotes cell survival; and other signalling pathways, which are required for KRAS-dependent tumour growth and endocytosis, and cytoskeletal organisation

Fig. 3

KRAS mutation in cancer. a The frequency of KRAS mutations across tumour types, including the mutation frequency of common sites and the subtype with the highest mutation rate in different tumour types. KRAS mutations are characterised by single-base missense mutations, 98% of which are found at codon 12, codon 13, or codon 61. Please refer to Table 1 for specific figures. b Specific mutant subtypes and percentages were represented in the top three cancers with the highest mutation rates of KRAS including pancreatic cancer, colorectal cancer, and nonsmall-cell lung cancer. c Frequency of co-occurring aberrations in KRAS mutant cells. Only a mutant prevalence of at least 3% is shown in addition to EGFR mutation, given the important effect of EGFR mutation on NSCLC. TP53: tumour protein p53 gene; DDR2: discoidin domain receptor tyrosine kinase 2 gene; MET: MNNG HOST Transforming gene; PIK3CA: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha gene; STK11: serine/threonine kinase 11 gene; KEAP1: kelch-like ECH-associated protein 1 gene; ATM: ATM serine/threonine kinase gene, PIK3CG: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma gene; ERBB4: erb-b2 receptor tyrosine kinase 4 gene; KDR: kinase insert domain receptor gene; KIT: KIT proto-oncogene receptor tyrosine kinase gene; NFE2L2 nuclear factor erythroid 2, like 2 gene; PDGFR previous symbol of PDGFRB (platelet-derived growth factor receptor beta gene). Data acquired from The Cancer Genome Atlas (pan-Cancer) from cBioPortal

Fig. 4

KRAS-mediated immune escape in tumour microenvironment. KRAS mediates immune escape in the tumour macroenvironment by upregulating PD-L1expression, downregulating MHC1expression of tumour cells, and enhancing the secretion of a variety of cytokines and chemokines to recruit immunosuppressive immune cells. The black arrow represents facilitation, and the opposite red arrow represents inhibition. MDSCs: myeloid-derived suppressor cells; Treg cells: regulatory T cells; IL-10: interleukin-10; TGF-β: transforming growth factor-β; GM-CSF: granulocyte-macrophage colony-stimulating factor; IL-23: interleukin-23

Fig. 5

Current targeted strategies for KRAS (G12C). a Despite the mutation occurring in KRAS, KRAS (G12C) still continues to perform the KRAS-GDP/GTP cycle. Covalent inhibitors such as AMG510 and MRTX849 lock KRAS (G12C) in inactivated GDP-bound state, thus decreasing functional KRAS. Another strategy is to increase the degradation of mutant KRAS (G12C) proteins. Based on the previously described KRAS (G12C) covalent inhibitors, LC-2, an endogenous KRAS (G12C) degrader, has been developed to promote KRAS (G12C) degradation. b The development and chemical structures of KRAS (G12C) inhibitors

Fig. 6

Combinational strategies for KRAS (G12C) inhibitors. The combined strategy of KRAS (G12C) inhibitors is mainly divided into four parts: combined with chemoradiotherapy, targeted therapy, immune therapy, and metabolic therapy

Fig. 7

Acquired resistance mechanism of covalent KRAS (G12C) inhibitors. The figure on the left blue background represents cells that are sensitive to KRAS (G12C) inhibitors, while the figure on right red background represents cells that are resistant to inhibitors. The black dotted line represents inhibition of KRAS signalling in the presence of KRAS (G12C) inhibitors. The solid red lines represent the resistance mechanisms identified after the use of KRAS (G12C) inhibitors, including the relief of ERK-mediated feedback inhibition, which reactivates the MAPK pathway by wild-type RAS (NRAS and HRAS) or new synthetic KRAS (G12C); the activation of other bypasses, such as PI3K activation by the IGFR–IRS1 pathway and secondary or additional mutations in KRAS. This figure generated from BioRender