Improving survival by exploiting tumour dependence on stabilized mutant p53 for treatment

Abstract

SUMMARYMissense mutations in p53 generate aberrant proteins with abrogated tumor suppressor functions that can also acquire oncogenic gain-of-functions (GOF) that promote malignant progression, invasion, metastasis and chemoresistance1–5. Mutant p53 (mutp53) proteins undergo massive constitutive stabilization specifically in tumors, which is the key requisite for GOF6–8. Although currently 11 million patients worldwide live with tumors expressing highly stabilized mutp53, it is unknown whether mutp53 is a therapeutic target in vivo.Here we use a novel mutp53 mouse model expressing an inactivatible R248Q hotspot mutation (floxQ) to show that tumors depend on sustained mutp53 expression. Upon Tamoxifen-induced mutp53 ablation, allo-transplanted and autochthonous tumors curb their growth, thus extending animal survival by 37%, and advanced tumors undergo apoptosis and tumor regression or stagnation.The HSP90/HDAC6 chaperone machinery, which is significantly upregulated in cancer compared to normal tissues, is a major determinant of mutp53 stabilization9–12. We show that long-term HSP90 inhibition significantly extends the survival of mutp53 Q/−2 and H/H (R172H allele3) mice by 59% and 48%, respectively, but not their respective p53−/− littermates. This mutp53-dependent drug effect occurs in H/H mice treated with 17DMAG+SAHA and in H/H and Q/− mice treated with the potent Hsp90 inhibitor ganetespib. Notably, drug activity correlates with induction of mutp53 degradation, tumor apoptosis and prevention of T-lymphomagenesis. These proof-of-principle data identify mutp53 as an actionable cancer-specific drug target.

Strong antitumor synergy between DNA crosslinking and HSP90 inhibition causes massive premitotic DNA fragmentation in ovarian cancer cells

“…1 Among these clients are tumor drivers such as mutant p53 (ref. 2) and MIF, 3 but also cell cycle regulators like Wee1(ref. 4) and Chk1, 5 as well as DNA repair proteins such as those governing the Fanconi Anemia DNA repair pathway.…”

Regulatory module involving FGF13, miR-504, and p53 regulates ribosomal biogenesis and supports cancer cell survival

“…Such enablers allow the cancer cell to reset its metabolic balance and achieve higher biosynthetic rates without going overboard. Concomitantly, these cells acquire an addiction to the enabler, as shown for other buffering proteins such as molecular chaperones (21,59), thus positioning such enablers as potential targets for cancer therapy.…”

2208 In vitro cytotoxic activities of the oral platinum(IV) prodrug oxoplatin and HSP90 inhibitor ganetespib against a panel of gastric cancer cell lines

“…Therefore, prevention of mutp53 stabilization by the inhibition of HSP90 may be an attractive target in cancer treatment [18][19][20]. During our study, we focused on the evaluation of gastric cancer cell lines which differ in their type and p53 mutation status.…”