APC/PIK3CA mutations and β-catenin status predict tankyrase inhibitor sensitivity of patient-derived colorectal cancer cells.

Autor: Chen, Mingjue, Mashima, Tetsuo, Oishi, Taichi, Muramatsu, Yukiko, Seto, Yosuke, Takamatsu, Manabu, Kawata, Naomi, Morino, Shun, Nakamura, Ayane, Inaba, Saori, Yuan, Xunmei, Maruyama, Kohei, Suzuki, Mai, Sato, Ayana, Yoshida, Haruka, Jang, Myung-Kyu, Mizutani, Anna, Takeuchi, Kengo, Yamaguchi, Kensei, Shirai, Fumiyuki
Zdroj: British Journal of Cancer; Jan2024, Vol. 130 Issue 1, p151-162, 12p
Abstrakt: Background: Aberrant WNT/β-catenin signaling drives carcinogenesis. Tankyrases poly(ADP-ribosyl)ate and destabilize AXINs, β-catenin repressors. Tankyrase inhibitors block WNT/β-catenin signaling and colorectal cancer (CRC) growth. We previously reported that 'short' APC mutations, lacking all seven β-catenin-binding 20-amino acid repeats (20-AARs), are potential predictive biomarkers for CRC cell sensitivity to tankyrase inhibitors. Meanwhile, 'Long' APC mutations, which possess more than one 20-AAR, do not predict inhibitor–resistant cells. Thus, additional biomarkers are needed to precisely predict the inhibitor sensitivity. Methods: Using 47 CRC patient-derived cells (PDCs), we examined correlations between the sensitivity to tankyrase inhibitors (G007-LK and RK-582), driver mutations, and the expressions of signaling factors. NOD.CB17-Prkdcscid/J and BALB/c-nu/nu xenograft mice were treated with RK-582. Results: Short APC mutant CRC cells exhibited high/intermediate sensitivities to tankyrase inhibitors in vitro and in vivo. Active β-catenin levels correlated with inhibitor sensitivity in both short and long APC mutant PDCs. PIK3CA mutations, but not KRAS/BRAF mutations, were more frequent in inhibitor–resistant PDCs. Some wild-type APC PDCs showed inhibitor sensitivity in a β-catenin-independent manner. Conclusions: APC/PIK3CA mutations and β-catenin predict the sensitivity of APC-mutated CRC PDCs to tankyrase inhibitors. These observations may help inform the strategy of patient selection in future clinical trials of tankyrase inhibitors. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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