Abstract
Tankyrase (TNKS) 1/2 are positive regulators of WNT signaling by controlling the activity of the ß-catenin destruction complex. TNKS inhibitors provide an opportunity to suppress hyperactive WNT signaling in tumors, however, they have shown limited anti-proliferative activity as a monotherapy in human cancer cell lines. Here we perform a kinome-focused CRISPR screen to identify potential effective drug combinations with TNKS inhibition. We show that the loss of CDK4, but not CDK6, synergizes with TNKS1/2 blockade to drive G1 cell cycle arrest and senescence. Through precise modelling of cancer-associated mutations using cytidine base editors, we show that this therapeutic approach is absolutely dependent on suppression of canonical WNT signaling by TNKS inhibitors and is effective in cells from multiple epithelial cancer types. Together, our results suggest that combined WNT and CDK4 inhibition might provide a potential therapeutic strategy for difficult-to-treat epithelial tumors.
Highlights
Almost all colorectal cancers (CRCs) carry activating mutations in the WNT pathway, most often due to loss-of-function truncations in the adenomatous polyposis coli (APC) tumor suppressor[1, 2]
We recently showed that restoring endogenous regulation of the WNT pathway by re-expressing normal levels of APC, is sufficient to induce disease regression in established colorectal cancers[8, 9]
Activation of the WNT pathway is a driver in many cancer types, colorectal cancer
Summary
Almost all colorectal cancers (CRCs) carry activating mutations in the WNT pathway, most often due to loss-of-function truncations in the adenomatous polyposis coli (APC) tumor suppressor[1, 2]. Numerous studies have shown that hyperactivation of the WNT pathway is an oncogenic driver in the intestine[3,4,5], and in many cases, suppression of WNT signaling is sufficient to induce cell differentiation[6] and tumor regression in animal models[7,8,9,10,11,12]. We recently showed that restoring endogenous regulation of the WNT pathway by re-expressing normal levels of APC, is sufficient to induce disease regression in established colorectal cancers[8, 9].
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