Dana-Farber Cancer Institute (DFCI): Discovery of Resistance Mechanisms: Breast Cancer

Resistance to targeted therapy is emerging as a bottleneck to achieving durable drug responses in cancer. The goal of the CTD2 Center at Dana Farber Cancer Institute is to identify mechanisms of resistance for both existing therapeutics as well as for emerging targets even prior to the identification of lead compounds. They aim to use this information to inform combinatorial treatments. In representative examples they have found that YAP1 leads to resistance after KRAS targeting and that PRKACA mediates resistance to HER2 therapy.

Kinase ORF Library Screening for resistance to HER2 targeted therapy

A systematic interrogation of mechanisms of resistance to suppression of HER2 was used to identify the major mechanisms of resistance to HER2-directed therapy.

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Experimental Approaches

Two kinome open reading frame (ORF) screens were conducted in parallel to identify genes that confer resistance to the lapatinib-like dual EGFR/HER2 inhibitor AEE788 and to suppression of HER2 with a short hairpin RNA (shRNA). Then a V5 epitope-tagged kinase ORF collection was used to identify genes that mediate resistance to these manipulations.

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Data

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For questions, please contact Joshua Dempster.

Last updated: September 14, 2018