Targeting RAS Mutant Colorectal Cancer with Dual Inhibition of MEK and CDK4/6

被引:33
作者
Sorokin, Alexey V. [1 ]
Marie, Preeti Kanikarla [1 ]
Bitner, Lea [1 ]
Syed, Muddassir [1 ]
Woods, Melanie [1 ]
Manyam, Ganiraju [2 ]
Kwong, Lawrence N. [3 ]
Johnson, Benny [1 ]
Morris, Van K. [1 ]
Jones, Philip [4 ]
Menter, David G. [1 ]
Lee, Michael S. [1 ]
Kopetz, Scott [1 ,5 ]
机构
[1] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, Houston, TX USA
[2] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX USA
[3] Univ Texas MD Anderson Canc Ctr, Dept Translat Mol Pathol, Houston, TX USA
[4] Univ Texas MD Anderson Canc Ctr, Inst Appl Canc Sci, Houston, TX USA
[5] Univ Texas MD Anderson Canc Ctr, Dept Gastrointestinal Med Oncol, 1515 Holcombe Blvd,Unit 426, Houston, TX 77030 USA
关键词
PLUS IRINOTECAN; CETUXIMAB; PHOSPHATASES; COMBINATION; XENOGRAFTS; THERAPY;
D O I
10.1158/0008-5472.CAN-22-0198
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
? KRAS and NRAS mutations occur in 45% of colorectal cancers, with combined MAPK pathway and CDK4/6 inhibition identified as a potential therapeutic strategy. In the current study, this combinatorial treatment approach was evaluated in a co-clinical trial in patient-derived xenografts (PDX), and safety was established in a clinical trial of binimetinib and palbociclib in patients with metastatic colorectal cancer with RAS mutations. Across 18 PDX models undergoing dual inhibition of MEK and CDK4/6, 60% of tumors regressed, meeting the co-clinical trial primary endpoint. Prolonged duration of response occurred predominantly in TP53 wild-type models. Clinical evaluation of binimetinib and palbociclib in a safety lead-in confirmed safety and provided preliminary evidence of activity. Prolonged treatment in PDX models resulted in feedback activation of receptor tyrosine kinases and acquired resistance, which was reversed with a SHP2 inhibitor. These results highlight the clinical potential of this combination in colorectal cancer, along with the utility of PDX-based co-clinical trial plat-forms for drug development. Significance: This co-clinical trial of combined MEK-CDK4/6 inhibition in RAS mutant colorectal cancer demonstrates therapeutic efficacy in patient-derived xenografts and safety in patients, identifies biomarkers of response, and uncovers targetable mechanisms of resistance.
引用
收藏
页码:3335 / 3344
页数:10
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