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Targeting Colon Cancers with Mutated BRAF and Microsatellite Instability

  • Paulo Matos
  • Peter JordanEmail author
Chapter
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 1110)

Abstract

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.

Keywords

Alternative splicing BRAF Microsatellite instability RAC1b Serrated polyp pathway 

Notes

Acknowledgements

Work in the authors’ laboratory was supported by Fundação para a Ciência e Tecnologia (FCT) [through centre grant UID/MULTI/04046/2013 to BioISI, contract ‘FCT Investigator’ to PM, and fellowship SFRH/BPD/63395/2009 to VG] and by the Portuguese association Maratona da Saúde – Cancro 2014 to PJ.

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© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Department of Chemistry and Biochemistry, Faculty of SciencesUniversity of LisbonLisbonPortugal
  2. 2.BioISI – Biosystems & Integrative Sciences Institute, Faculty of SciencesUniversity of LisbonLisbonPortugal
  3. 3.Department of Human GeneticsNational Health Institute ‘Dr. Ricardo Jorge’LisbonPortugal

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