Mutation-selective BRAF inhibitors can paradoxically activate the mitogen-activated protein kinase (MAPK) signalling pathway in cells that lack BRAF mutations but bear other MAPK pathway signalling drivers such as mutations of RAS. This can result in the promotion of cancer, as serious adverse effects of these inhibitors. This activation also has immune consequences such as promoting T lymphocyte proliferation and immune recognition of cancer. Indeed BRAFi in combination with Immune-based therapy has been proposed as a means of improving clinical outcomes.
To reduce the risk of second cancers new BRAF inhibitors (PLX8394 & PLX7904), dubbed “Paradox Breakers”, have been developed to inhibit V600 mutated oncogenic BRAF without causing the paradoxical reactivation of MAPK signalling.
We recently reported a patient whose metastatic colon cancer (BRAFwt/ KRASG12D) was promoted in-vivo and in-vitro by BRAF inhibitor therapy (dabrafenib, GSK2118436). Here we compare the effect of the BRAF inhibitors PLX4032 (vemurafenib) and PLX4720 (vemurafenib-analog) with that of the paradox breakers, on colon cancer cell lines including a cell line derived from this patient (LM-Col-1) and on a panel of melanoma cell lines with differing mutational backgrounds.
We demonstrate that PLX8394 and PLX7904 retain on-target BRAF V600-mutant inhibition in melanoma cells without paradoxically promoting MAPK signalling of BRAFwt colon adenocarcinomas in contrast to vemurafenib and its analog. This indicates that these “paradox breaker” BRAF inhibitors are likely to offer an effective and safer treatment option; especially in patients with a previous history of malignancies that carry activating mutations of RAS.
If paradox breakers do not promote immune cell activation however, it is possible that this could blunt the clinical benefit of these agents in patients long-term. We are therefore now studying the effect of these inhibitors on immune cell function including T lymphocytes proliferation and cytokine production in vitro.