Modelling drug sensitivity and resistance in tumour-derived cell lines


Session type:

Jeff Settleman1
1Genentech, South San Francisco, USA


Accumulating evidence points to the importance of genomic heterogeneity across human tumors as a critical determinant of the variable clinical response to molecularly-targeted cancer therapies. We have been using cancer cell lines as a model system for examining the relationship between underlying genotypes and sensitivity to candidate anti-cancer agents. These studies have revealed the utility of large panels of cancer cell lines to capture the genomic heterogeneity of human cancer and to identify clinically-relevant genotype-phenotype relationships. These studies have begun to shed light on mechanisms underlying sensitivity as well as de novo and acquired resistance to a variety of small molecule inhibitors. Using this same platform, we have also identified a mechanism of reversible drug “tolerance” that involves a distinct chromatin state displayed transiently by small sub-populations of cancer cells. This drug-tolerant state can be disrupted by chromatin-modifying agents, potentially yielding a therapeutic opportunity to prevent or delay the development of more stable genetically-conferred drug resistance mechanisms.