Circumventing TP53 Dysfunction: Targeting Cell Survival Pathways

Loss or mutation of TP53 is one of the commonest mutations in cancers and is intimately associated with poor prognosis, disease progression and the acquisition of chemo-resistance. In this context, del17p - marker for TP53 dysfunction - is strongly associated with poor outcomes in patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM). TP53 is critical for the normal cellular responses (growth arrest, apoptosis and senescence amongst others) to stress (“guardian of the genome”) and when it is mutated, these essential cellular responses are subverted. A critical downstream consequence of activating TP53 is apoptosis (programmed cell death), principally the mitochondrial BCL2-regulated pathway to apoptosis. Thus, TP53 dysfunction leads to the impairment of apoptosis, now recognized as a cancer hallmark. Moreover, BCL2 itself is universally overexpressed in CLL. Impressive responses have recently been observed in patients treated with small molecule inhibitors of BCL2, firstly with navitoclax (ABT-263) and more recently, venetoclax (ABT-199). The so-called BH3 mimetic compounds act by mimicking the action of the BH3-only proteins, natural antagonists of BCL2 and its relatives such as BCLXL and MCL1. Since the BH3 mimetic compounds act downstream of TP53, they should act regardless of a tumor’s TP53 status. Strikingly, cases of del17p CLL have shown robust responses that are indistinguishable from other cases, strongly suggesting that targeting BCL2 is a highly promising approach to treat these challenging cases that normally have dismal outcomes. Venetoclax (ABT-199) is also active in some cases of mantle cell lymphoma, acute myeloid leukemia and MM. However, only some cases of MM rely on BCL2 whereas most MM cells are dependent on another BCL2-related protein, MCL1. I shall review data from recent laboratory and clinical studies that explore and explain the efficacy of the BH3 mimetic compounds in tumors that harbor dysfunctional TP53. Based on the success in targeting BCL2 for CLL, I will also explore the approaches taken to target MCL1 and discuss prospects for using such strategies as therapy for del17p MM.