Novel mutant KRAS addiction signature predicts response to the combination of ERBB and MEK inhibitors in lung and pancreatic cancers

被引：4
|
作者：
Tyc, Katarzyna M. [1 ,2 ]
Kazi, Aslamuzzaman [1 ]
Ranjan, Alok [1 ]
Wang, Rui [1 ]
Sebti, Said M. [1 ]
机构：
[1] Virginia Commonwealth Univ, Massey Canc Ctr, Dept Pharmacol & Toxicol, Richmond, VA 23298 USA
[2] Virginia Commonwealth Univ, Massey Canc Ctr, Dept Biostat & Bioinformat Shared Resource Core, Richmond, VA 23298 USA
来源：
ISCIENCE | 2023年 / 26卷 / 03期
关键词：
SET ENRICHMENT ANALYSIS; GENE; SUPPRESSION; AMPHIREGULIN; DEPENDENCY; REGULATORS; MUTATION;
D O I：
10.1016/j.isci.2023.106082
中图分类号：
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号：
07 ; 0710 ; 09 ;
摘要：
KRAS mutations are prevalent in pancreatic and lung cancers, but not all mutant (mt) KRAS tumors are addicted to mt KRAS. Here, we discovered a 30-gene tran-scriptome signature "KDS30"that encodes a novel EGFR/ERBB2-driven signaling network and predicts mt KRAS, but not NRAS or HRAS, oncogene addiction. High KDS30 tumors from mt KRAS lung and pancreatic cancer patients are enriched in genes upregulated by EGFR, ERBB2, mt KRAS or MEK. EGFR/ERBB2 (neratinib) and MEK (cobimetinib) inhibitor combination inhibits tumor growth and prolongs mouse survival in high, but not low, KDS30 mt KRAS lung and pancreatic xeno-grafts, and is synergistic only in high KDS30 mt KRAS patient-derived organoids. Furthermore, mt KRAS high KDS30 lung and pancreatic cancer patients live significantly shorter lives than those with low KDS30. Thus, KDS30 can identify lung and pancreatic cancer patients whose tumors are addicted to mt KRAS, and predicts EGFR/ERBB2 and MEK inhibitor combination response.
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页数：25
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