曲美替尼
克拉斯
MEK抑制剂
结直肠癌
PI3K/AKT/mTOR通路
癌症研究
医学
癌症
MAPK/ERK通路
药理学
激酶
细胞凋亡
生物
内科学
生物化学
细胞生物学
作者
Susmita Ghosh,Fan Fan,Reid T. Powell,Jason Roszik,Yong Sung Park,Clifford Stephan,Manu Sebastian,Lin Tan,Alexey V. Sorokin,Philip L. Lorenzi,Scott Kopetz,Lee M. Ellis,Rajat Bhattacharya
出处
期刊:Molecular Cancer Therapeutics
[American Association for Cancer Research]
日期:2023-06-13
卷期号:22 (8): 962-975
被引量:1
标识
DOI:10.1158/1535-7163.mct-23-0110
摘要
Mutations in KRAS are found in more than 50% of tumors from patients with metastatic colorectal cancer (mCRC). However, direct targeting of most KRAS mutations is difficult; even the recently developed KRASG12C inhibitors failed to show significant benefit in patients with mCRC. Single agents targeting mitogen-activated protein kinase kinase (MEK), a downstream mediator of RAS, have also been ineffective in colorectal cancer. To identify drugs that can enhance the efficacy of MEK inhibitors, we performed unbiased high-throughput screening using colorectal cancer spheroids. We used trametinib as the anchor drug and examined combinations of trametinib with the NCI-approved Oncology Library version 5. The initial screen, and following focused validation screens, identified vincristine as being strongly synergistic with trametinib. In vitro, the combination strongly inhibited cell growth, reduced clonogenic survival, and enhanced apoptosis compared with monotherapies in multiple KRAS-mutant colorectal cancer cell lines. Furthermore, this combination significantly inhibited tumor growth, reduced cell proliferation, and increased apoptosis in multiple KRAS-mutant patient-derived xenograft mouse models. In vivo studies using drug doses that reflect clinically achievable doses demonstrated that the combination was well tolerated by mice. We further determined that the mechanism underlying the synergistic effect of the combination was due to enhanced intracellular accumulation of vincristine associated with MEK inhibition. The combination also significantly decreased p-mTOR levels in vitro, indicating that it inhibits both RAS-RAF-MEK and PI3K-AKT-mTOR survival pathways. Our data thus provide strong evidence that the combination of trametinib and vincristine represents a novel therapeutic option to be studied in clinical trials for patients with KRAS-mutant mCRC.Our unbiased preclinical studies have identified vincristine as an effective combination partner for the MEK inhibitor trametinib and provide a novel therapeutic option to be studied in patients with KRAS-mutant colorectal cancer.
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