Oral Presentation The 44th Lorne Conference on Protein Structure and Function 2019

Acquired BCL2 mutations that confer resistance to Venetoclax treatment (#19)

Richard W Birkinshaw 1 2 , Jia-nan Gong 1 2 , Piers Blombery 3 4 5 , Mary Ann Anderson 1 2 3 , Rachel Thijssen 1 2 , Peter Colman 1 2 , Andrew W Roberts 1 2 3 6 7 , David C S Huang 1 2 , Peter E Czabotar 1 2
  1. The Walter and Eliza Hall Institute of Medical Research, Melbourne
  2. Dept of Medical Biology, University of Melbourne, Melbourne
  3. Clinical Haematology, Peter MacCallum Cancer Centre and Royal Melbourne Hospital, Melbourne
  4. Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne
  5. Dept of Pathology, Peter MacCallum Cancer Centre, Melbourne
  6. Centre for Cancer Research, University of Melbourne, Melbourne
  7. Victorian Comprehensive Cancer Centre, Melbourne

The BCL2 inhibitor venetoclax is approved for the treatment of CLL. Venetoclax competes with pro-apoptotic proteins for BCL2 binding, releasing pro-apoptotic proteins in CLL cells, providing targeted removal of the cancerous cells. We recently identified a BCL2 Gly101Val mutation from patients on venetoclax clinical trials that pre-empted relapse and clinical disease progression [1]. We used surface plasmon resonance to show this novel Gly101Val BCL2 mutation reduces the venetoclax affinity by ~180 fold, whilst maintaining affinity for pro-apoptotic proteins. These findings have been confirmed in ex-vivo culture and in-vitro cellular models. The Gly101Val mutation thereby causes selective reduction of venetoclax affinity allowing acquired resistance to the therapy.

We have solved structures of venetoclax bound to BCL2 wild-type, the BCL2 Gly101Val mutation and a BCL2 Phe104Leu mutation [1, 2]. We show that even though these mutations affect different regions of the BCL2 structure they both provide selective reduction in venetoclax affinity. The BCL2 Gly101Val structure revealed unexpected changes to venetoclax binding, allowing the design of additional BCL2 mutations that rescue venetoclax binding in the presence of the Gly101Val mutation. These structures reveal two independent mechanisms for selective reduction of venetoclax affinity that can confer resistance to the therapy.

 

  1. Blombery, P., et al., Acquisition of the recurrent Gly101Val mutation in BCL2 confers resistance to venetoclax in patients with progressive chronic lymphocytic leukemia., Cancer Discovery, accepted for publication.
  2. Fresquet, V., et al., Acquired mutations in BCL2 family proteins conferring resistance to the BH3 mimetic ABT-199 in lymphoma.,Blood. 2014. p. 4111-4119.