Abstract
Osimertinib sensitive and resistant NSCLC NCI-H1975 clones were used to model osimertinib acquired resistance in humanized mice and delineate potential resistance mechanisms. No new EGFR mutations or loss of the EGFR T790M mutation were found in resistant clones. Resistant tumors in humanized mice were initially partially responsive to osimertinib, then aggressive tumor regrowth occurred accompanied by an immunosuppressive tumor microenvironment. 3-phosphoinositide-dependent kinase 1 (PDK1) was identified as a potential driver of osimertinib acquired resistance, and its selective inhibition by BX795 and CRISPR gene knock out, sensitized resistant clones and a patient derived xenograft (PDX) with acquired resistance to osimertinib. PDK1 knock-out dysregulated PI3K/Akt/mTOR signaling, promoted cell cycle arrest at the G1 phase, and inhibited nuclear translocation of yes-associated protein (YAP). Higher expression of PDK1 was found in patients with progressive disease following osimertinib treatment. PDK1 is a central upstream regulator of two critical drug resistance pathways: PI3K/AKT/mTOR and YAP.
Competing Interest Statement
Jack A. Roth reports receiving a commercial research grant from The University of Texas MD Anderson Cancer Center, sponsored research agreement from Genprex, Inc, has ownership interest (including stock, patents, etc.) in Genprex, Inc., and is a consultant/advisory boardmember for Genprex, Inc. Trever G Bivona is an advisor to Array/Pfizer, Revolution Medicines, Springworks, Jazz Pharmaceuticals, Relay Therapeutics, Rain Therapeutics, Engine Biosciences, and receives research funding from Novartis, Strategia, Kinnate, and Revolution Medicines. Jonathan Wesley Riess is an advisor to Blueprint, Beigene, Daiichi Sankyo, EMD Serono, Janssen, Turning Point, Regeneron, Sanofi Aventis and a consultant to Blueprint, Novartis, Boehringer Ingelheim. He also receives research funding from Merck, Novartis, Spectrum, Revolution Medicine, AstraZeneca. The other authors disclosed no potential conflicts of interest or competing interests.
