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Cancer Institute Seminar Series - Dr Luca Gerosa
18 May 2020, 3:00 pm–4:00 pm
Dr Luca Gerosa, Harvard Medical School, presents: 'Adaptive ERK pulses enable persistence of BRAF-mutant melanoma cells during targeted therapy.' This is an online event.
Event Information
Open to
- All
Organiser
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Veronica Dominguez
Hosted by: Prof Bart Vanhaesebroeck
Emerging evidence suggests that persisted cells adapting by non-genetic mechanisms to anti-cancer drugs constitute a reservoir for the development of frank genetic resistance. Here, we show that within hours of exposure to RAF and MEK inhibitors, BRAF V600E melanoma cells undergo adaptive changes involving disruption of negative feedback and pulsatile reactivation of the MAPK pathway, so that ERK phosphorylation is transiently high in some cells to drive their survival and persistent slow proliferation. Quantitative proteomics and computational modelling show that adaptive ERK pulses are possible due to the co-existence in cells of two MAPK cascade configurations: one driven by BRAF V600E that is drug-sensitive and a second driven by transmembrane receptors that is drug-resistant. Taken together, these findings reveal a vulnerability of targeted therapies to adaptive MAPK signalling in single cells that might underlie disease persistence.
Seminar catch up
If you missed the the live seminar, a recording is available:
About the Speaker
Dr Luca Gerosa
at Harvard Medical School
Dr Gerosa is a Postdoctoral Fellow in the lab of Peter Sorger in the Department of Systems Biology and the Laboratory of Systems Pharmacology at Harvard Medical School. The goal of his postgraduate research is to understand the non-genetic mechanisms by which cancer cells adapt and become resistant to targeted drug therapies. By building computational models that integrate multiplex biochemical measurement and single-cell experimental data, Luca focuses on unraveling the contribution of signalling and transcriptional circuits to the insurgency of adaptive resistance, fractional killing and oncogene addiction in cancer cells.