RAS genes in colorectal carcinoma: pathogenesis, testing guidelines and treatment implications

Abstract

The RAS family is among the most commonly mutated genes in all human malignancies including colon cancer. In normal cells, RAS proteins act as a link in the intracellular signal transduction initiated by binding of growth factors to cell membrane receptors mediating cell survival. RAS isoproteins have great morphological similarities, but despite that, they are thought to have different functions in different tissues. RAS mutations, as supported by several studies including animal models, have a role in the development and progression of colorectal cancer. The detection of RAS mutations in patients with colorectal carcinoma, specifically KRAS and NRAS, has significant clinical implications. It is currently recommended that patients with colon cancer who are considered for antiepidermal growth factor receptor monoclonal antibodies, get RAS mutation testing since only those with wildtype-RAS genes benefit from such treatment. Despite decades of research, there is currently no effective and safe treatment that directly targets RAS-mutated neoplasms. Multiple therapeutic approaches directed against RAS mutations are currently experimental, including a promising immunotherapy study using T-cells in patients with metastatic colon cancer.

Antitumorigenic Effects of Inhibiting Ephrin Receptor Kinase Signaling by GLPG1790 against Colorectal Cancer Cell Lines In Vitro and In Vivo

“…As such, there is an urgent need for new therapeutic strategies to treat CRC. Eph, from the largest family of RTKs that by binding membrane bound ligands named ephrins, regulates many cellular functions through the modulation of several signal transduction pathways including the RAS/ERKs/MAPKs pathway [4,5] known to sustain CRC [24]. CRC cells express high levels of different Eph proteins including EphA2, a known marker of poor prognosis in advanced CRC and a potentially critical therapeutic target for the treatment of CRC [7][8][9].…”

ASPP1 deficiency promotes epithelial-mesenchymal transition, invasion and metastasis in colorectal cancer

“…Colorectal cancer (CRC) has the third highest incidence of malignant tumors and was globally the second leading cause of cancer death in 2018 34 . Development of CRC is a result of interactions between genetics and environmental factors 35 . The RAS family (KRAS, HRAS, NRAS), are frequently mutated in human cancer, approximately 25% of human malignances harbor RAS mutations 35 .…”

“…Development of CRC is a result of interactions between genetics and environmental factors 35 . The RAS family (KRAS, HRAS, NRAS), are frequently mutated in human cancer, approximately 25% of human malignances harbor RAS mutations 35 . In CRC, KRAS and NRAS mutations are found in approximately 44.7% and 7.5% of cases respectively 35 and RAS has not only been found to drive tumour progression but also is key in tumour maintenance [36][37][38] .…”

“…The RAS family (KRAS, HRAS, NRAS), are frequently mutated in human cancer, approximately 25% of human malignances harbor RAS mutations 35 . In CRC, KRAS and NRAS mutations are found in approximately 44.7% and 7.5% of cases respectively 35 and RAS has not only been found to drive tumour progression but also is key in tumour maintenance [36][37][38] . Lifestyle factors, including smoking, diet, lack of exercise, combined with an aging population all contribute to an increased risk of CRC 39 .…”

Microsatellite instability and mismatch repair deficiency in the era of precision immuno-oncology

“…It is well established that many genetic factors provide critical information to guide antineoplastic therapy decisions for CRC patients. The presence of RAS mutations is a contraindication for anti-EGFR therapy [5]. CRC patients with dMMR or MSI-H, both sporadic and Lynch Syndrome-related cases, have better stage-adjusted prognoses but do not benefit from 5-fluorouracil chemotherapy.…”