KRAS-related proteins in pancreatic cancer

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• 作者：Karen M. Mann^a ; ^{kmmann@houstonmethodist.org} ; Haoqiang Ying^b ; Joseph Juan^c ; Nancy A. Jenkins^a ; Neal G. Copeland^a
• 关键词：PDAC ; pancreatic ductal adenocarcinoma ; KRAS ; Kirsten rat sarcoma viral oncogene ; GEMM ; genetically engineered mouse model ; SB_PDAC ; Sleeping Beauty insertional mutagenesis model of pancreatic cancer ; GAP ; GTPase activating protein ; GEF ; guanine nucleotide exchange factor ; EGFR ; Epidermal growth factor receptor ; MEK ; mitogen-activated protein kinase kinase ; ERK ; extracellular signal-related kinase ; PI3K ; phosphoinositide 3-kinase
• 刊名：Pharmacology & Therapeutics
• 出版年：2016
• 出版时间：December 2016
• 年：2016
• 卷：168
• 期：Complete
• 页码：29-42
• 全文大小：1384 K
• 卷排序：168

文摘

Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease with a high mortality rate. Genetic and biochemical studies have shown that RAS signaling mediated by KRAS plays a pivotal role in disease initiation, progression and drug resistance. RAS signaling affects several cellular processes in PDAC, including cellular proliferation, migration, cellular metabolism and autophagy. 90% of pancreatic cancer patients harbor somatic oncogenic point mutations in KRAS, which lead to constitutive activation of the molecule. Pancreatic cancers lacking KRAS mutations show activation of RAS via upstream signaling through receptor mediated tyrosine kinases, like EGFR, and in a small fraction of patients, oncogenic activation of the downstream B-RAF molecule is detected. RAS-stimulated signaling of RAF/MEK/ERK, PI3K/AKT/mTOR and RalA/B is active in human pancreatic cancers, cancer cell lines and mouse models of PDAC, although activation levels of each signaling arm appear to be variable across different tumors and perhaps within different subclones of single tumors. Recently, several targeted therapies directed towards MEK, ERK, PI3K and mTOR have been assayed in pancreatic cancer cell lines and in mouse models of the disease with promising results for their ability to impede cellular growth or delay tumor formation, and several inhibitors are currently in clinical trials. However, therapy-induced cross activation of RAS effector molecules has elucidated the complexities of targeting RAS signaling. Combinatorial therapies are now being explored as an approach to overcome RAS-induced therapeutic resistance in pancreatic cancer.