用 PROTAC 靶向 TNKS 支架功能，克服催化抑制剂在结直肠癌中的局限
Targeting tankyrase scaffolding in the β-catenin destruction complex by PROTAC overcomes the limitation of catalytic inhibitors in colorectal cancer
研究指出，TNKS 催化抑制剂在多种结直肠癌模型中疗效有限，原因在于催化抑制阻止了 TNKS 的周转，使其在 β-catenin 降解复合物（DC）中积累；TNKS 的支架功能进而诱导 AXIN 形成 puncta、使 DC 刚性化，并阻碍 β-catenin 的周转。作者用化学方法诱导 TNKS 降解，在不形成 AXIN puncta 的情况下稳定 AXIN，从而更深入地抑制 WNT/β-catenin 通路活性，以及携带 APC 功能缺失突变的结直肠癌细胞的增殖。
来源：eLife · doi.org
Aberrant WNT/β-catenin signaling drives tumorigenesis and metastasis in cancer. Although enzymatic inhibitors of tankyrase (TNKS) effectively block AXIN degradation and stabilize the β-catenin destruction complex (DC), they have demonstrated limited efficacy in various colorectal cancer (CRC) models. Here, we demonstrate that, unexpectedly, the induction of AXIN puncta represents a major barrier to achieving therapeutic efficacy. Mechanistically, catalytic inhibition of TNKS prevents TNKS turnover and drives its accumulation in the DC, wherein the scaffolding function of TNKS induces AXIN puncta formation, rigidifies the DC, and impedes β-catenin turnover. Chemically induced degradation of TNKS overcomes this limitation by stabilizing AXIN without puncta formation, providing a deeper suppression of the WNT/β-catenin pathway activity and the proliferation of CRC cells harboring dysfunctional APC mutations. Collectively, these findings provide an explanation for the unsatisfactory outcomes of drugging the WNT/β-catenin signaling pathway by TNKS inhibitors and highlight TNKS degradation as a promising approach to treat WNT/β-catenin-driven CRC.