Resistance To Avapritinib In PDGFRA GI Stromal Tumor Is Caused By Secondary Mutations In The PDGFRA Kinase Domain

In a recent publication, in the Journal Cancer Discovery, January 2021, investigators wanted to determine the mutation profile in patients with GI stromal tumors, with underlying activating mutations of PDGFRA, treated with avapritinib. Avapritinib has activity in patients with underlying D842V mutations. While the majority of patients are noted to not develop resistance, a small subset of patients becomes resistant. 

The investigators collected tumor and plasma samples from 7 patients who have progressed on avapritinib, with confirmed underlying PDGFRA mutations or had progressed on imatinib, had secondary resistance mutations with PDGFRA exons 13, 14 and 15.  These mutations are thought to interfere with avapritinib binding.  Secondary PDGFRA mutations causing V658A, N659K, Y676C, G860R substitutions were found in 2 or more patients each, thought to represent recurrent mechanisms of drug resistance.  

The investigators felt that for patients who became refractory to avapritinib, the tumor still were dependent on PDGFRA oncogenic signaling.  The future pathway would be to target the protein stability of PDGFRA, or inhibit PDGFRA-dependent signaling pathways to overcome avapritinib resistance.

https://cancerdiscovery.aacrjournals.org/content/early/2020/12/22/2159-8290.CD-20-0487

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