Susceptibility to autophagy inhibition is enhanced by dual IGF1R and MAPK/ERK inhibition in pancreatic cancer.
Susceptibility to autophagy inhibition is enhanced by dual IGF1R and MAPK/ERK inhibition in pancreatic cancer.
复制标题
胰腺癌中 IGF1R 和 MAPK/ERK 的双重抑制增强了对自噬抑制的敏感性。
DOI：
10.1080/15548627.2022.2042782
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发表时间：
2022
期刊：
影响因子：
13.3
通讯作者：
Bryant,KirstenL
中科院分区：
文献类型：
--
作者：
Stalnecker,ClintA;Coleman,MichaelF;Bryant,KirstenL
Macroautophagy/autophagy is upregulated in pancreatic ductal adenocarcinoma (PDAC) and PDAC growth is reliant on autophagy. However, autophagy inhibitors as monotherapy have shown limited clinical efficacy. To identify targets that sensitize PDAC cells to autophagy inhibition, we performed a CRISPR-Cas9 genetic loss-of-function screen in cells treated with the lysosomal inhibitor chloroquine (CQ) and identified IGF1R as a sensitizer. IGF1R inhibition increases autophagic flux and sensitivity to CQ-mediated growth suppression bothin vitroandin vivo. Importantly, sensitization is further enhanced with the concurrent inhibition of MAPK1/ERK2 (mitogen-activated protein kinase 1)-MAPK3/ERK1. IGF1R and MAPK/ERK inhibition converge on suppression of glycolysis. In summary, IGF1R and MAPK/ERK signaling promotes resistance to CQ/HCQ in PDAC, and their dual inhibition increases sensitivity to autophagy inhibitors.
