突变型p53特异性的TAZ/TEAD通路依赖性作为三阴性乳腺癌的治疗机会

Background: Missense mutations in the TP53 tumor suppressor gene lead to gain-of-function (GOF) properties that affect differently tumor growth, metastasis, and resistance to therapies, but targeting mutant p53 is still a major clinical challenge. Using MCF10A cells expressing 10 prevalent TP53 mutations, we performed integrated phenotypic and molecular analyses to identify targetable genes and pathways in Triple-Negative Breast Cancer (TNBC) harboring specific p53 mutations and discovered TAZ/TEAD dysregulation as the key determinants of cell invasion and drug resistance. Methods: Based on our previous findings, we measured activation status of TEAD in drug-sensitive and resistant mutant p53-expressing cells and evaluated the differential drug response against single or combination treatment of the TEAD inhibitor GNE-7883 and the standard-of-care, doxorubicin. The TEAD activity was verified with a luciferase reporter, and cell viability was measured with phosphatase assays. Results: The TEAD-luciferase reporter assay showed that p53 G245S and R273H mutants but not R175H or Y163C had elevated activity of the Hippo pathway effector, TEAD. Treatment of GNE-7883 robustly inhibited the hyper-activation of TEAD specifically in the G245S and R273H cells. In viability assays, these "TEAD-addicted" cells uniquely displayed sensitivity to high dose of GNE-7883 monotherapy (IC₅₀ ~2.5 µM). Moreover, they also showed hypersensitivity to doxorubicin (IC₅₀ = 14 nM), compared to the cells with wild-type p53 (IC₅₀ = 250 nM). We were able to develop a synergistic, low-dose combination regimen (3.5 nM doxorubicin + 0.625-1.25 µM GNE-7883) that was cytotoxic for the cells with G245S and R273H mutants yet had minimal to no activity in the wild-type cells. In contrast, R175H and Y163C mutants were resistant to TEAD inhibition, requiring higher doses of GNE-7883 to observe an anti-cancer activity, emphasizing the selectivity of this vulnerability. Conclusion: We have established a synthetic lethal interaction between TEAD inhibition for a defined chemo-sensitive subgroup of GOF p53 mutants, G245S and R273H, for which the Hippo/TEAD pathway states appear to be a key dependency. We propose a precision approach to therapeutic strategy of combining low, non-toxic dose doxorubicin with TEAD inhibition to increase efficacy while decreasing toxicity. Our ongoing work is to validate these findings in more physiologically relevant models.