UCL Cancer Institute Seminar Series

The emergence of drug resistance ultimately proves fatal for the majority of patients, and therefore the early detection of resistance and the identification of novel strategies to overcome the underlying mechanisms is a subject of intense activity. A decade of clinical studies has revealed that the evolution of drug resistance in cancer often follows predictable pathways and is more constrained that previously imagined.

In many cases, the resistance mechanisms are themselves amenable to being targeted therapeutically. One can imagine exploiting the evolutionary dynamics of cancer cells whereby the use of one drug is used to deliberately steer the cells towards a new vulnerability which is then targeted. Such an approach is only feasible if the means exist to systematically define all of the evolutionary pathways a cancer cell will exploit to develop drug resistance and begin to identify ways to target these new vulnerabilities. For these reasons, there is renewed interest in the use of multiple genome-wide forward genetic screens to deliberately engineer into the cancer genome mutational events that cause drug resistance. Such screens, if sufficiently unbiased, could in theory capture a greater breadth of genetic resistance mechanisms for any drug. 

The molecular characterisation of drug resistant tumors in cancer patients has revealed a landscape composed of the loss-of-function, gain-of-function and point mutation-mediated perturbation of genes, with often no one mechanism being predominant. Therefore, in theory, capturing the entire breadth of resistance effectors for any drug would require multiple genetic screens to be executed in parallel and the outputs aggregated into a single view of the landscape of resistance pathways for that drug. 

Here we describe the use of multiple forward genetic screens executed in parallel in cancer cells to identify those genes, and their cognate pathways, that when overexpressed, silenced or mutated confer resistance in BRAF mutant colon cancer to a BRAF/MEK/EGFR inhibitor combination currently being tested in clinical trials. We demonstrate that this resistance landscape is finite, relatively constrained to a small number of pathways and that it is possible to exploit the evolutionary dynamics that underpins the clonal expansion of drug resistant cells therapeutically.

Hosted by: Professors Bart Vanhaesebroeck and Daniel Hochhauser

The seminar will be followed by a sandwich buffet lunch

For further information: www.sanger.ac.uk/people/directory/mcdermott-ultan

Selected publications

1. Jonathan Brammeld et al. Genome-wide chemical mutagenesis screens allow unbiased saturation of the cancer genome and identification of drug resistance mutations. Genome Research (accepted for publication). Biorxiv doi: https://doi.org/10.1101/066555

2. Garraway LA, Jänne PA. Circumventing cancer drug resistance in the era of personalized medicine. Cancer Discov. 2012;2(3):214-26.

3. Ophir Shalem et al. Genome-Scale CRISPR-Cas9 Knockout Screening in Human Cells. Science. 2014 Jan 3; 343(6166): 84–87.

Location

Courtyard Café
UCL Cancer Institute
Paul O'Gorman Building
London, WC1E 6DD

Contact: Veronica Dominguez v.dominguez@ucl.ac.uk

This seminar has been part-sponsored by Merck, the Biomedical Research Centre and Cancer Research UK.