Abstract SY04-03: Improving survival by exploiting tumor dependence on stabilized mutant p53 in mouse models

Abstract

Abstract Missense mutations in p53 generate aberrant proteins with abrogated tumour suppressor functions that can also acquire oncogenic gain-of-function activities that promote malignant progression, invasion, metastasis and chemoresistance (1-5). Mutant p53 (mutp53) proteins undergo massive constitutive stabilization specifically in tumours, which is the key requisite for the acquisition of gain-of- functions activities (6-8). Although currently 11 million patients worldwide live with tumours expressing highly stabilized mutp53, it is unknown whether mutp53 is a therapeutic target in vivo. Here we use a novel mutp53 knockin mouse model expressing a conditional inactivatable R248Q hotspot mutation (called floxQ; present in human cancers) to show that tumours depend on sustained mutp53 protein expression. Upon Tamoxifen-induced mutp53 ablation, allotransplanted and autochthonous tumours curb their growth, thus extending animal survival by 37%, and advanced tumours undergo apoptosis and tumour regression or stagnation. The HSP90/HDAC6 chaperone machinery, which is significantly upregulated in cancer compared with normal tissues, is a major determinant of mutp53 stabilization (9-12). We show that long-term HSP90 inhibition significantly extends the survival of hotspot mutp53 Q/- (R248Q allele; Ref 2) and H/H (R172H allele; Ref 3) mice by 59% and 48%, respectively, but not their corresponding p53 -/- (also known as Trp53 -/-) littermates. This mutp53-dependent drug effect occurs in tumor-bearing H/H mice treated with 17DMAG/SAHA, and in H/H and Q/- mice treated with the potent Hsp90 inhibitor ganetespib (the latter given as a once-weekly monotherapy). Notably, drug activity correlates with induction of mutp53 degradation, tumour cell apoptosis and strong prevention of T-cell lymphomagenesis. Together, these findings support the notion that tumors expressing mutp53 depend on it for tumor survival and maintenance, and fundamentally differ in their oncogenic wiring from p53-null tumors. Moreover, and surprisingly, the mechanism of action of these pleiotropic Hsp90 inhibitors in this specific setting is largely via targeting mutp53. Missense mutp53 is highly expressed in ∼50% of all human tumors. One therapeutic strategy, considered for nearly two decades, is to develop small compounds capable of restoring the lost wildtype function of mutp53 proteins (13). In the face of this daunting and still elusive goal, the results presented here show that eliminating stabilized mutp53 protein has positive therapeutic effects in vivo, even in the absence of a wildtype allele, since such tumors show exploitable dependence on its gain-of-function. Moreover, targeting Hsp90 might represent the first and currently only viable clinical strategy to achieve this goal. Overall, these proof-of-principle data identify mutp53 as a potentially actionable cancer-specific drug target.