Strategies to tackle RAS-mutated metastatic colorectal cancer

Abstract

The RAS oncogene is among the most commonly mutated in cancer. RAS mutations are identified in about half of patients diagnosed with metastatic colorectal cancer (mCRC), conferring poor prognosis and lack of response to anti-epidermal growth factor receptor (EGFR) antibodies. In the last decades, several investigational attempts failed in directly targeting RAS mutations, thus RAS was historically regarded as 'undruggable'. Recently, novel specific KRAS^G12C inhibitors showed promising results in different solid tumors, including mCRC, renewing interest in this biomarker as a target. In this review, we discuss different strategies of RAS targeting in mCRC, according to literature data in both clinical and preclinical settings. We recognized five main strategies focusing on those more promising: direct RAS targeting, targeting the mitogen-activated protein kinase (MAPK) pathway, harnessing RAS through immunotherapy combinations, RAS targeting through metabolic pathways, and finally other miscellaneous approaches. Direct KRAS^G12C inhibition is emerging as the most promising strategy in mCRC as well as in other solid malignancies. However, despite good disease control rates, tumor response and duration of response are still limited in mCRC. At this regard, combinational approaches with anti-epidermal growth factor receptor drugs or checkpoint inhibitors have been proposed to enhance treatment efficacy, based on encouraging results achieved in preclinical studies. Besides, concomitant therapies increasing metabolic stress are currently under evaluation and expected to also provide remarkable results in RAS codon mutations apart from KRAS^G12C. In conclusion, based on hereby reported efforts of translational research, RAS mutations should no longer be regarded as 'undruggable' and future avenues are now opening for translation in the clinic in mCRC.

Keywords: KRAS; RAS; adagrasib; colorectal cancer; sotorasib.

Figure 1

Prevalence of RAS mutations in metastatic colorectal cancer. Data were retrieved from the COSMIC database (https://cancer.sanger.ac.uk/cosmic) consulted on 27 February 2021. The percentage of mutated samples for point mutations regarding the ‘KRAS’, ‘NRAS’, and ‘HRAS’ genes was collected from COSMIC v92 using auto-filtering for ‘large intestinal’ tissue type, and ‘cecum’ or ‘left’ or ‘right’ or ‘colon’ or ‘rectum’ sub-site, and ‘carcinoma’ histology, and ‘adenocarcinoma’ sub-histology. For KRAS mutations, the most common codon variants were also collected. Raw data are available in Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2021.100156. MT, mutant; WT, wild-type.

Figure 2

Main therapeutic strategies targeting RAS-mutant metastatic colorectal cancer. Five therapeutic strategies targeting RAS-mutant metastatic colorectal cancer were identified and categorized by different pharmacodynamic interferences with the RAS signal: direct RAS targeting, targeting the MAPK pathway, harnessing RAS through immunotherapy combinations, RAS targeting through metabolic pathways, and other miscellaneous approaches. The main molecular targets are shown and grouped according to the most suitable anti-RAS therapeutic strategy. Created with BioRended.com. Bcl-XL, B-cell lymphoma-extra large; CDK, cyclin-dependent kinase; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; DDR, DNA damage response and repair; EGFR, epidermal growth factor receptor; ERK, extracellular signal-regulated kinase; GF, growth factor; GDP, guanosine diphosphate; GTP, guanosine triphosphate; MAPK, mitogen-activated protein kinase; mCRC, metastatic colorectal cancer; MDM2, murine double minute 2; MGMT, O⁶-methylguanine-DNA methyl-transferase; mTOR, mammalian target of rapamycin; PARP, poly (ADP-ribose) polymerase; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; PI3K, phosphatidylinositol 3-kinase; PTEN, phosphatase and tensin homolog; RTK, receptor tyrosine kinase; SHP2, Src homology region 2 domain-containing phosphatase-2; SOS1, sevenless homologue 1.