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

Katarzyna M Tyc; Aslamuzzaman Kazi; Alok Ranjan; Rui Wang; Said M Sebti

doi:10.1016/j.isci.2023.106082

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

iScience. 2023 Jan 31;26(3):106082. doi: 10.1016/j.isci.2023.106082. eCollection 2023 Mar 17.

Authors

Katarzyna M Tyc¹, Aslamuzzaman Kazi¹, Alok Ranjan¹, Rui Wang¹, Said M Sebti¹

Affiliation

¹ Department of Pharmacology and Toxicology, and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.

Abstract

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 transcriptome 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 xenografts, 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.

Keywords: Cancer; Transcriptomics.