In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 7_Supplement ( 2023-04-04), p. 491-491
Abstract:
Mitogen-activated protein kinase (MEK) inhibitors have shown promising results in KRAS-mutated cancers with constitutive activation of the RAS/RAF/MEK pathway. However, the intrinsic and acquired resistance to MEK inhibitors is frequently observed in clinical trials. Wnt/β-catenin signaling hyper-activation is reported to be responsible for such resistance in colorectal cancer (CRC). Herein, we introduce a novel tankyrase inhibitor STP1002 to revert the intrinsic and acquired resistance to MEK inhibitors in KRAS-mutated CRC. Dual combination of STP1002 and MEK inhibitor synergistically reduced the oncogenic activity of KRAS (G12V or G12D)-mutated CRC cell lines. Data also showed that concomitant treatment with STP1002 and MEK inhibitor dramatically inhibited tumor growth of KRAS (G12V)-mutated CRC xenograft animal models. Moreover, the combination treatment sensitized the acquired MEK inhibitor-resistant CRC cells and suppressed the Wnt/YAP pathway which is the bypass mechanism of MEK inhibitor resistance. Dual combination of STP1002 and MEK inhibitor is a promising candidate to overcome resistance to MEK inhibitors in colorectal cancer with KRAS-G12V/G12D mutations. The phase 1 clinical trial study is ongoing in order to show safety margin. Citation Format: Young-Ju Kwon, Dong Young Kim, Uk-Il Kim, Xue Meng, Ho Kyun Lee, Hyung Tae Bang, Jae-Sung Kim, Kyungjin Kim. Tankyrase-selective inhibitor STP1002 reverses resistance to MEK inhibitors in colorectal cancer with KRAS mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 491.
Type of Medium:
Online Resource
ISSN:
1538-7445
DOI:
10.1158/1538-7445.AM2023-491
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2023
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
