期刊
ONCOTARGET
卷 8, 期 43, 页码 73419-73432出版社
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.20621
关键词
Alisertib; DLL3; rovalpituzumab tesirine; SCLC; TTF1
资金
- NIH/NCI [P30CA016672, 1-R01-CA207295]
- University of Texas-Southwestern and MD Anderson Cancer Center Lung SPORE [5 P50 CA070907]
- MD Anderson Cancer Center Physician Scientist Award
- Lee Clark Fellowship of The MD Anderson Cancer Center
- Jeane F. Shelby Scholarship Fund
- NCI Cancer Clinical Investigator Team Leadership Award [P30 CA016672]
- Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy's Center for Professional Education and Training
- LUNGevity Foundation
- Rexanna Foundation
- Sidney Kimmel Foundation for Cancer Research
- V Foundation for Cancer Research
- ACS Research Scholar Award [RSG-13-300-01-TBG]
- NIH [R01CA187457]
- Damon Runyon Cancer Research Foundation [DRR-26-13]
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.
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