Poster Presentation 35th Lorne Cancer Conference 2023

Whole genome CRISPR/Cas9 screening to understand resistance to BH3-mimetic drugs in lymphoma (#133)

Sarah T Diepstraten 1 2 , Yexuan Deng 1 2 , Catherine Chang 1 , Marco Herold 1 2 , Andreas Strasser 1 2 , Gemma L Kelly 1 2
  1. Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
  2. Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia

One hallmark of cancer is dysregulation of the intrinsic apoptosis, or cell death, pathway. This pathway is mediated by proteins of the BCL-2 family, which includes both pro-apoptotic and pro-survival factors, the levels of which are usually carefully maintained to determine whether a cell lives or dies.

BH3-mimetics are exciting anti-cancer drugs which directly bind and inhibit specific pro-survival proteins, tipping the balance of the apoptosis pathway towards favouring cell death. As testament to their efficacy, BH3-mimetic drugs targeting the pro-survival protein BCL-2 have been approved by many regulatory agencies worldwide for the treatment of chronic lymphocytic leukaemia and acute myeloid leukaemia. New BH3-mimetics targeting MCL-1, an essential survival factor for a wide range of haematological malignancies, are currently in clinical trials for diverse blood cancers. However, emerging clinical data suggests that while BH3-mimetics are initially highly effective at killing cancer cells, drug resistance frequently develops over long-term treatment, resulting in patient relapse.

We are using a systematic approach to explore how lymphoma cells can become resistant to BH3-mimetic drugs targeting BCL-2 or MCL-1. We employ whole-genome CRISPR/Cas9 knockout and activation screens in mouse and human models of lymphoma to identify factors which contribute to drug resistance. We recently identified the tumour suppressor protein p53, among others, as an important mediator of the cellular response to BH3-mimetic drugs. Using this information, we have identified therapeutic vulnerabilities in drug-resistant lymphoma cells, which can then be targeted in combination with BH3-mimetic drugs to improve the outcomes of patients with blood cancers.