RT Journal Article
SR Electronic
T1 A focal adhesion kinase-YAP signaling axis drives drug tolerant persister cells and residual disease in lung cancer
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.10.23.465573
DO 10.1101/2021.10.23.465573
A1 Franziska Haderk
A1 Celia Fernández-Méndez
A1 Lauren Čech
A1 Johnny Yu
A1 Ismail M. Meraz
A1 Victor Olivas
A1 Dora Barbosa Rabago
A1 D. Lucas Kerr
A1 Carlos Gomez
A1 David V. Allegakoen
A1 Juan Guan
A1 Khyati N. Shah
A1 Kari A. Herrington
A1 Oghenekevwe M. Gbenedio
A1 Shigeki Nanjo
A1 Mourad Majidi
A1 Whitney Tamaki
A1 Julia K. Rotow
A1 Caroline E. McCoach
A1 Jonathan W. Riess
A1 J. Silvio Gutkind
A1 Tracy T. Tang
A1 Leonard Post
A1 Bo Huang
A1 Pilar Santisteban
A1 Hani Goodarzi
A1 Sourav Bandyopadhyay
A1 Calvin J. Kuo
A1 Jeroen P. Roose
A1 Wei Wu
A1 Collin M. Blakely
A1 Jack A. Roth
A1 Trever G. Bivona
YR 2021
UL http://biorxiv.org/content/early/2021/10/24/2021.10.23.465573.abstract
AB Targeted therapy is effective in many tumor types including lung cancer, the leading cause of cancer mortality. Paradigm defining examples are targeted therapies directed against non-small cell lung cancer (NSCLC) subtypes with oncogenic alterations in EGFR, ALK and KRAS. The success of targeted therapy is limited by drug-tolerant tumor cells which withstand and adapt to treatment and comprise the residual disease state that is typical during treatment with clinical targeted therapies. Here, we integrate studies in patient-derived and immunocompetent lung cancer models and clinical specimens obtained from patients on targeted therapy to uncover a focal adhesion kinase (FAK)-YAP signaling axis that promotes residual disease during oncogenic EGFR-, ALK-, and KRAS-targeted therapies. FAK-YAP signaling inhibition combined with the primary targeted therapy suppressed residual drug-tolerant cells and enhanced tumor responses. This study unveils a FAK-YAP signaling module that promotes residual disease in lung cancer and mechanism-based therapeutic strategies to improve tumor response.Competing Interest StatementT.G.B. 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. J.A.R. is consultant and has equity in Genprex, Inc., patents issued and pending. C.M.B. is a consultant to Amgen, and Blueprint Medicines, and receives research funding from AstraZeneca, Novartis, Takeda, Spectrum, Roche, and Mirati. J.P.R. is a co-founder and scientific advisor of Seal Biosciences, Inc. and advisor for the Mark Foundation for Cancer Research. C.J.K. is an advisor to Surrozen, Inc., Mozart Therapeutics and NextVivo. J.S.G. is a member of the advisory board of Oncoceutics and Domain Therapeutics. J.W.R. is an advisor to Blueprint, Beigene, Daiichi Sankyo, EMD Serano, Turning Point, and Janssen, and is a consultant to Blueprint, Novartis, and Boehringer Ingelheim. J.W.R. receives research funding from Merck, Novartis, Spectrum, Revolution Medicine, AstraZeneca, and GlaxoSmithKline. T.T.T. and L.P. are employees of Vivace Therapeutics and have equity interest in Vivace Therapeutics.