TP53 Loss Creates Susceptibility to Anti–Pol II Therapy in Colorectal Cancer

Genetic perturbation of the tumor suppressor gene TP53 is one of the most common events in human carcinogenesis; however, efforts to reactivate p53 have thus far been unsuccessful. Liu and colleagues hypothesized that hemizygous deletion of the chromosome 17p13 region harboring TP53 also encompasses neighboring genes required for cell survival, and found that POLR2A, which encodes the largest subunit of RNA polymerase II (Pol II), is commonly codeleted with TP53 in human colorectal cancer. Hemizygous loss of POLR2A was tightly associated with decreased POLR2A expression and rendered cells susceptible to inhibition of POLR2A. Treatment of colorectal cancer cell lines with low doses of the specific POLR2A inhibitor α-amanitin or shRNA-mediated knockdown of POLR2A resulted in decreased proliferation and induction of cell death in cells with hemizygous POLR2A deletion (POLR2A^loss), but only modestly affected POLR2A^neutral cells. Consistent with these findings, exogenous expression of POLR2A in POLR2A^loss cells rescued resistance to α-amanitin, whereas hemizygous deletion of POLR2A sensitized POL2RA^neutral cells to α-amanitin independent of TP53 status. In addition, inhibition of POLR2A specifically enhanced the cytotoxic effects of standard chemotherapeutics in POLR2A^loss cells. This sensitivity to POLR2A inhibition was recapitulated in vivo using siRNA-mediated POLR2A knockdown, which selectively suppressed the growth of established POLR2A^loss xenograft tumors. Furthermore, low-dose treatment with an α-amanitin–based antibody–drug conjugate targeting epithelial cell adhesion molecule, which exhibits increased efficacy and reduced toxicity compared with α-amanitin, induced complete regression of POLR2A^loss tumors, but not POLR2A^neutral tumors, in an orthotopic model of human colorectal cancer. Overall, these observations support the hypothesis that collateral loss of POLR2A due to TP53 deletion renders cells susceptible to α-amanitin therapy and suggest that this therapeutic strategy may be broadly applied across cancer types.

Liu Y, Zhang X, Han C, Wan G, Huang X, Ivan C, et. al. TP53 loss creates therapeutic vulnerability in colorectal cancer. Nature 2015;520:697–701.

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