作者
Craig M Goodwin, Andrew M Waters, Jennifer E Klomp, Sehrish Javaid, Kirsten L Bryant, Clint A Stalnecker, Kristina Drizyte-Miller, Bjoern Papke, Runying Yang, Amber M Amparo, Irem Ozkan-Dagliyan, Elisa Baldelli, Valerie Calvert, Mariaelena Pierobon, Jessica A Sorrentino, Andrew P Beelen, Natalie Bublitz, Mareen Lüthen, Kris C Wood, Emanuel F Petricoin III, Christine Sers, Autumn J McRee, Adrienne D Cox, Channing J Der
发表日期
2023/1/4
期刊
Cancer research
卷号
83
期号
1
页码范围
141-157
出版商
American Association for Cancer Research
简介
Mutational loss of CDKN2A (encoding p16INK4A) tumor-suppressor function is a key genetic step that complements activation of KRAS in promoting the development and malignant growth of pancreatic ductal adenocarcinoma (PDAC). However, pharmacologic restoration of p16INK4A function with inhibitors of CDK4 and CDK6 (CDK4/6) has shown limited clinical efficacy in PDAC. Here, we found that concurrent treatment with both a CDK4/6 inhibitor (CDK4/6i) and an ERK–MAPK inhibitor (ERKi) synergistically suppresses the growth of PDAC cell lines and organoids by cooperatively blocking CDK4/6i-induced compensatory upregulation of ERK, PI3K, antiapoptotic signaling, and MYC expression. On the basis of these findings, a Phase I clinical trial was initiated to evaluate the ERKi ulixertinib in combination with the CDK4/6i palbociclib in patients with advanced PDAC (NCT03454035). As …
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CM Goodwin, AM Waters, JE Klomp, S Javaid… - Cancer research, 2023