Common oncogenic mutations in colorectal cancer: drivers of carcinogenesis and potential therapeutic targets

Colorectal cancer (CRC) is marked by an intricate interaction of genetic mutations with the tumor microenvironment (TME). This review will provide updated insights into the effects of major mutations in CRC patients, including MMR, APC, KRAS, BRAF, PIK3CA, and TP53, on tumor progression and highlight their dynamic interactions with the TME, which can modulate, mask, or convert therapeutic sensitivity or resistance. Mutations in the KRAS and BRAF genes, for instance, have been associated with adverse outcomes and therapy resistance in CRC patients. Tumor profiling is significant for predicting prognosis and treatment responses, since mutation-specific crosstalk with the TME clarifies opportunities for personalized treatment strategies. Moreover, combination therapies targeting the multifaceted pathways of tumor cells and TME components have the potential to overcome drug resistance. New approaches in therapy are highly promising, especially in targeting the Wnt/β-catenin pathway, restoring APC function, and exploiting synthetic lethal interactions with truncated APC using next-generation small-molecule inhibitors, such as TASIN-1. More research is necessary to fully elucidate the interconnections among specific mutations, the TME, and treatment responsiveness to develop personalized therapies.