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Authors
Advisor(s)
Abstract(s)
The subgroup of colon cancer (CRC) characterized by mutation in the BRAF gene and high mutation rate in the genomic DNA sequence, known as the microsatellite instability (MSI) phenotype, accounts for roughly 10% of the patients and derives from polyps with a serrated morphology. In this review, both features are discussed with regard to therapeutic opportunities. The most prevalent cancer-associated BRAF mutation is BRAF V600E that causes constitutive activation of the pro-proliferative MAPK pathway. Unfortunately, the available BRAF-specific inhibitors had little clinical benefit for metastatic CRC patients due to adaptive MAPK reactivation. Recent contributions for the development of new combination therapy approaches to pathway inhibition will be highlighted. In addition, we review the promising role of the recently developed immune checkpoint therapy for the treatment of this CRC subtype. The MSI phenotype of this subgroup results from an inactivated DNA mismatch repair system and leads to frameshift mutations with translation of new amino acid stretches and the generation of neo-antigens. This most likely explains the observed high degree of infiltration by tumour-associated lymphocytes. As cytotoxic lymphocytes are already part of the tumour environment, their activation by immune checkpoint therapy approaches is highly promising.
Description
Keywords
Colorectal Cancer BRAF MSI immunotherapy RAC1b Vias de Transdução de Sinal e Patologias Associadas
Pedagogical Context
Citation
In: Jordan P. (ed). Targeted Therapy of Colorectal Cancer Subtypes. Springer, Cham, 2018, pp. 7-21. (Advances in Experimental Medicine and Biology; vol. 1110). Doi: 10.1007/978-3-030-02771-1_2
Publisher
Springer International Publishing