2007 – INFORMING THERAPEUTIC APPROACHES FOR P53 DEFECTIVE BLOOD CANCERS

Abstract

Mutations in the tumour suppressor TP53 are common in many cancers, including aggressive blood cancers, and confer poor responses to chemotherapy. Newer BH3-mimetic drugs, such as the BCL-2 inhibitor Venetoclax, were postulated to be effective therapy for TP53 mutant blood cancers since these drugs initiate apoptosis downstream of TP53 and therefore should function agnostic of TP53 status. However recent data from our lab and others indicate wild-type TP53 is required for maximal cancer cell killing by BH3-mimetic drugs.

Using pre-clinical models of several blood cancers and CRISPR/Cas9 approaches, we interrogated the role of TP53 in the apoptotic response to BH3-mimetic drugs. We found that TP53 is not needed for BH3-mimetics to induce apoptosis via mitochondrial outer membrane permeabilization (MOMP). However, TP53 becomes activated downstream of MOMP, leading to induction of the pro-apoptotic BH3-only proteins and a second wave of apoptosis that reinforces killing of the cancer cells. Blood cancers with mutant TP53 cannot induce this enforcing wave of apoptosis and are therefore more likely to survive and contribute to relapse.

Through these analyses we identified an alternative complementary pathway to activate apoptosis using STING agonist drugs. We found that STING agonists could induce BH3-only protein expression in a TP53-independent manner, boosting the pro-apoptotic signal. Combining STING agonists with BH3-mimetic drugs led to highly effective killing of mouse B cell lymphomas, human NK/T cell lymphomas and patient-derived Acute Myeloid Leukemia blasts, even those that were mutated for TP53. Since STING agonists are already in clinical trials to induce anti-tumour immunity, we anticipate repurposing them to boost apoptosis alongside BH3-mimetic drugs in clinical trials for blood cancer patients would be effective and relatively straight forward.