Synergistic tumor suppression by combined inhibition of telomerase and CDKN1A

Significance Over 90% of cancer cells express telomerase, which is required for their survival. However, telomerase inhibitors alone have so far failed to provide any significant clinical benefit. Therefore, identifying and targeting genes that can enhance the effects of telomerase inhibitors will greatly benefit a large population of cancer patients. We find that simultaneous inhibition of p21 and telomerase synergistically suppresses tumor growth. We also show that our approach is useful for treating p53 mutant cancers, when used with therapies that restore the function of mutant p53. We anticipate that simultaneous targeting of p21 and telomerase will overcome the current limitation of single-agent telomerase therapeutics and provide an effective method to treat cancers that rely on telomerase activity for survival. Tumor suppressor p53 plays an important role in mediating growth inhibition upon telomere dysfunction. Here, we show that loss of the p53 target gene cyclin-dependent kinase inhibitor 1A (CDKN1A, also known as p21WAF1/CIP1) increases apoptosis induction following telomerase inhibition in a variety of cancer cell lines and mouse xenografts. This effect is highly specific to p21, as loss of other checkpoint proteins and CDK inhibitors did not affect apoptosis. In telomerase, inhibited cell loss of p21 leads to E2F1- and p53-mediated transcriptional activation of p53-upregulated modulator of apoptosis, resulting in increased apoptosis. Combined genetic or pharmacological inhibition of telomerase and p21 synergistically suppresses tumor growth. Furthermore, we demonstrate that simultaneous inhibition of telomerase and p21 also suppresses growth of tumors containing mutant p53 following pharmacological restoration of p53 activity. Collectively, our results establish that inactivation of p21 leads to increased apoptosis upon telomerase inhibition and thus identify a genetic vulnerability that can be exploited to treat many human cancers containing either wild-type or mutant p53.

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