Understanding cancer drug resistance with functional genomic screens: Application to MAPK inhibition in cutaneous melanoma.

Combined BRAF and MEK inhibition is an effective treatment for BRAF-mutant cutaneous melanoma. However, most patients progress on this treatment due to drug resistance. Here, we applied the transposon system to understand how melanoma evades MAPK inhibition.

SRC-RAC1 signaling drives drug resistance to BRAF inhibition in de-differentiated cutaneous melanomas.

Rare gain-of-function mutations in RAC1 drive drug resistance to targeted BRAF inhibition in cutaneous melanoma. Here, we show that wildtype RAC1 is a critical driver of growth and drug resistance, but only in a subset of melanomas with elevated markers of de-differentiation. Similarly, SRC inhibition also selectively sensitized de-differentiated melanomas to BRAF inhibition.

Machine learning approach informs biology of cancer drug response.

Background: The mechanism of action for most cancer drugs is not clear. Large-scale pharmacogenomic cancer cell line datasets offer a rich resource to obtain this knowledge. Here, we present an analysis strategy for revealing biological pathways that contribute to drug response using publicly available pharmacogenomic cancer cell line datasets.

Src-Dependent DBL Family Members Drive Resistance to Vemurafenib in Human Melanoma.

The use of selective BRAF inhibitors (BRAFi) has produced remarkable outcomes for patients with advanced cutaneous melanoma harboring a mutation. Unfortunately, the majority of patients eventually develop drug-resistant disease. We employed a genetic screening approach to identify gain-of-function mechanisms of BRAFi resistance in two independent melanoma cell lines.

A simplified transposon mutagenesis method to perform phenotypic forward genetic screens in cultured cells.

Background: The introduction of genome-wide shRNA and CRISPR libraries has facilitated cell-based screens to identify loss-of-function mutations associated with a phenotype of interest. Approaches to perform analogous gain-of-function screens are less common, although some reports have utilized arrayed viral expression libraries or the CRISPR activation system. However, a variety of technical and logistical challenges make these approaches difficult for many labs to execute.