Molecular targeted therapy of BRAF-mutant colorectal cancer

Abstract

Over the past two decades, the molecular characterization of metastatic colorectal cancer (mCRC) has been revolutionized by the routine implementation of RAS and BRAF tests. As a result, it is now known that patients with mCRC harboring BRAF mutations experience a poor prognosis. Although it accounts for only 10% of mCRC, this group is heterogeneous; only the BRAF- V600E mutation, also observed in melanoma, is associated with a very poor prognosis. In terms of treatment, these patients do not benefit from therapeutics targeting the epidermal growth factor receptor (EGFR). In first-line chemotherapy, there are two main options; the first one is to use a triple chemotherapy combination of 5-fluorouracil, irinotecan, and oxaliplatin, with the addition of bevacizumab, because post hoc analysis of randomized trials have reported interesting results. The other option is to use double chemotherapy plus bevacizumab, since anti-EGFR seems to have modest activity in these patients. Only a small percentage of patients who experience failure of this first-line treatment receive second-line treatment. Monotherapy with BRAF inhibitors has failed in this setting, and different combinations have also been tested. Using the rationale that BRAF inhibitor monotherapy fails due to feedback activation of the EGFR pathway, BRAF inhibitors have been combined with anti-EGFR agents plus or minus MEK inhibitors; however, the results did not live up to the hopes raised by the concept. To date, the best results in second-line treatment have been obtained with a combination of vemurafenib, cetuximab, and irinotecan. Despite these advances, further improvements are needed.

Comprehensive review of targeted therapy for colorectal cancer

“…In contrast to RAS mutations, BRAF mutations, mostly comprising the V600E alteration, were found in 5-10% of metastatic CRC cases and cause activation of downstream MAPK regardless of RAS status. [51][52][53][54] Activation of PI3K by RAS or direct activation by EGFR transforms the second messenger phosphatidylinositolbisphosphate into phosphatidylinositol-trisphosphate (PIP3) through phosphorylation. PIP3 interacts with the SH3 domain of serine/threonine kinase PKB (also called AKT) recruited to the cell membrane.…”

BRAF Mutated Colorectal Cancer: New Treatment Approaches

“…It is known that the RAS/RAF/MEK/ERK signaling cascade, also known as the mitogen-activated protein kinase (MAPK) pathway, plays an essential role in cellular proliferation, differentiation, survival, and apoptosis [ 35 , 36 ] ( Figure 1 ).…”

NTRK Fusions in Central Nervous System Tumors: A Rare, but Worthy Target

“…Traditionally, tumor diagnosis and prognostic evaluation, as well as therapeutic management, were addressed by histological examination alone, which was based on tumor morphology and complementary immunohistochemical profiling. Nowadays this approach is no longer adequate for complete tumor characterization since molecular profiling has become necessary for optimal patient management [1][2][3][4][5]. As a result, diagnostic algorithms are undergoing substantial changes for many tumor types: this molecular revolution has been fully undertaken by the latest 2016 World Health Organization (WHO) classification of central nervous system (CNS) neoplasms, as molecular markers (e.g., IDH1/IDH2 (Isocitrate dehydrogenase 1/2), 1p/19q codeletion, ATRX (transcriptional regulator ATRX), TP53 (tumor protein p53) etc.)…”