Harnessing the power of human tumor-derived cell lines for the rational design of cancer therapies

Abstract

In 2002, a mutated constitutively active form of the proto-oncogene BRAF kinase (BRAFV600E) was discovered in ~50% of patients with melanoma. Just last year, the FDA approved an inhibitor and a companion genetic test to treat metastatic melanomas that are positive for this mutation. The rational selection of drugs based on specific genetic variation(s) within a tumor represents the advent of personalized cancer therapeutics. Clearly, this is the way of the future but much work remains to be carried out – a fact that is also illustrated by the BRAFV600E case study. While regression of BRAFV600E tumors in a vast majority of metastatic melanoma patients treated with BRAF inhibitors is encouraging vis-a-vis efficacy of targeted cancer therapeutics, the response is transient and the tumors inevitably recur. In vitro studies have shown that resistance also arises when BRAF inhibitors are combined with therapeutics targeted to other members of the MAP kinase (MAPK) pathway. This can probably be attributed to the selection of resistant mutants from the extensive genetic diversity of tumors within a single patient with metastatic melanoma (Yancovitz et al., 2012). One potential strategy to prevent such recurrence is to hit multiple targets with a cocktail of drugs that are rationally selected to match the complete complement of oncogenic mutations within the heterogeneous tumor cell population. Rational design of such drug cocktails will undoubtedly benefit from understanding of the assorted mechanisms by which resistance develops: additional mutations, epigenetic changes, modification of drug metabolism or clearance, or switching to alternative pathways. However, for a targeted approach to be effective, it will ultimately have to be paired with technologies to comprehensively genotype the entire diversity of mutations within the tumor cell population (Baslan et al., 2012; Navin et al., 2011).