Protein expression of TTF1 and cMYC define distinct molecular subgroups of small cell lung cancer with unique vulnerabilities to aurora kinase inhibition, DLL3 targeting, and other targeted therapies

Abstract

// Robert J. Cardnell 1 , Lerong Li 2 , Triparna Sen 1 , Rasha Bara 1 , Pan Tong 2 , Junya Fujimoto 3 , Abbie S. Ireland 4 , Matthew R. Guthrie 4 , Sheila Bheddah 5 , Upasana Banerjee 1 , Nene N. Kalu 1 , You-Hong Fan 1 , Scott J. Dylla 5 , Faye M. Johnson 1,6 , Ignacio I. Wistuba 3 , Trudy G. Oliver 4 , John V. Heymach 1 , Bonnie S. Glisson 1 , Jing Wang 2,4,* and Lauren A. Byers 1,6,* 1 Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 2 Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 3 Department of Molecular Translational Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA 4 Department of Oncological Sciences, University of Utah, Huntsman Cancer Institute, Salt Lake City, UT, USA 5 AbbVie StemCentrx, LLC, San Franciso, CA, USA 6 The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA * Co-senior authors Correspondence to: Lauren A. Byers, email: // Keywords : Alisertib, DLL3, rovalpituzumab tesirine, SCLC, TTF1 Received : July 04, 2017 Accepted : August 14, 2017 Published : September 01, 2017 Abstract Small cell lung cancer (SCLC) is a recalcitrant cancer for which no new treatments have been approved in over 30 years. While molecular subtyping now guides treatment selection for patients with non-small cell lung cancer and other cancers, SCLC is still treated as a single disease entity. Using model-based clustering, we found two major proteomic subtypes of SCLC characterized by either high thyroid transcription factor-1 (TTF1)/low cMYC protein expression or high cMYC/low TTF1. Applying “drug target constellation” (DTECT) mapping, we further show that protein levels of TTF1 and cMYC predict response to targeted therapies including aurora kinase, Bcl2, and HSP90 inhibitors. Levels of TTF1 and DLL3 were also highly correlated in preclinical models and patient tumors. TTF1 (used in the diagnosis lung cancer) could therefore be used as a surrogate of DLL3 expression to identify patients who may respond to the DLL3 antibody-drug conjugate rovalpituzumab tesirine. These findings suggest that TTF1, cMYC or other protein markers identified here could be used to identify subgroups of SCLC patients who may respond preferentially to several emerging targeted therapies.