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.

KRAS-G12C Mutation in One Real-Life and Three Population-Based Nordic Cohorts of Metastatic Colorectal Cancer

“…The clinical relevance of KRAS-G12C is unclear (10)(11)(12)(13)(14)(15)(16)(17). The frequency of KRAS-G12C has been reported to be 2%-8% in large databases of molecularly analyzed CRCs (12,14,18,19). In hospital-based series, the proportion of KRAS-G12C tumors was 2%-4% of all mCRC tumors (11,15,16,20), whereas greater variability was seen in the proportion of the KRAS-mutated population (6%-17%) (11,13,16,17,(20)(21)(22).…”

Mutant RAS and the tumor microenvironment as dual therapeutic targets for advanced colorectal cancer

“…However, this might be hampered by increased toxicity (supplementary table 3). Multiple combinations of MEK inhibitors with agents targeting the PI3K pathway have been tested-all with disappointing results [107].…”

Targeting KRAS: Crossroads of Signaling and Immune Inhibition

“…Another cancer type that commonly accompanies KRAS mutation is colorectal cancer, and KRAS G12C mutation occurs in approximately 8% of metastatic colorectal cancers with KRAS mutation. [ 28 ] A recent comprehensive study[ 29 ] analyzed patients with colorectal cancer molecularly and clinically elucidated that the progression-free survival of patients with KRAS G12C mutation was poorer than those with KRAS non-G12C mutation, suggesting innate resistance to chemotherapy for this subpopulation in colorectal cancer. However, a robust description of clinical features of G12C mutation not only in colorectal cancer but also in other cancer types remains scarce, and further understanding of pathophysiological features, clinical characteristics such as responsiveness to systemic therapy, and prognosis of KRAS G12C mutations across a variety of cancer types, is needed.…”