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3-Phosphoinositide-dependent kinase 1 drives acquired resistance to osimertinib

View ORCID ProfileIsmail M. Meraz, Mourad Majidi, View ORCID ProfileBingliang Fang, Feng Meng, Lihui Gao, RuPing Shao, Renduo Song, Feng Li, View ORCID ProfileMin Jin Ha, Qi Wang, Jing Wang, Elizabeth Shpall, Sung Yun Jung, Franziska Haderk, View ORCID ProfilePhilippe Gui, Jonathan Wesley Riess, Victor Olivas, View ORCID ProfileTrever G Bivona, View ORCID ProfileJack A. Roth
doi: https://doi.org/10.1101/2021.12.10.472153
Ismail M. Meraz
1Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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  • For correspondence: imeraz@mdanderson.org
Mourad Majidi
1Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Bingliang Fang
1Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Feng Meng
1Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Lihui Gao
1Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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RuPing Shao
1Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Renduo Song
1Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Feng Li
1Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Min Jin Ha
2Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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  • ORCID record for Min Jin Ha
Qi Wang
3Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Jing Wang
3Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Elizabeth Shpall
4Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Sung Yun Jung
5Department of Biochemistry, Baylor College of Medicine, Houston, TX, USA
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Franziska Haderk
6Department of Medicine, University of California, San Francisco, San Francisco; CA, USA
7Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco; CA, USA
8Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA
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Philippe Gui
6Department of Medicine, University of California, San Francisco, San Francisco; CA, USA
7Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco; CA, USA
8Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA
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Jonathan Wesley Riess
9University of California Davis Comprehensive Cancer Center, Sacramento, CA, USA
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Victor Olivas
6Department of Medicine, University of California, San Francisco, San Francisco; CA, USA
7Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco; CA, USA
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Trever G Bivona
6Department of Medicine, University of California, San Francisco, San Francisco; CA, USA
7Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco; CA, USA
8Department of Cellular and Molecular Pharmacology, University of California, San Francisco, San Francisco, CA, USA
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Jack A. Roth
1Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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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.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted December 13, 2021.
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3-Phosphoinositide-dependent kinase 1 drives acquired resistance to osimertinib
Ismail M. Meraz, Mourad Majidi, Bingliang Fang, Feng Meng, Lihui Gao, RuPing Shao, Renduo Song, Feng Li, Min Jin Ha, Qi Wang, Jing Wang, Elizabeth Shpall, Sung Yun Jung, Franziska Haderk, Philippe Gui, Jonathan Wesley Riess, Victor Olivas, Trever G Bivona, Jack A. Roth
bioRxiv 2021.12.10.472153; doi: https://doi.org/10.1101/2021.12.10.472153
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3-Phosphoinositide-dependent kinase 1 drives acquired resistance to osimertinib
Ismail M. Meraz, Mourad Majidi, Bingliang Fang, Feng Meng, Lihui Gao, RuPing Shao, Renduo Song, Feng Li, Min Jin Ha, Qi Wang, Jing Wang, Elizabeth Shpall, Sung Yun Jung, Franziska Haderk, Philippe Gui, Jonathan Wesley Riess, Victor Olivas, Trever G Bivona, Jack A. Roth
bioRxiv 2021.12.10.472153; doi: https://doi.org/10.1101/2021.12.10.472153

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