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Journal article
Therapeutic Challenge with a CDK 4/6 Inhibitor Induces an RB-Dependent SMAC-Mediated Apoptotic Response in Non-Small Cell Lung Cancer
Clinical cancer research, v 24(6), pp 1402-1414
15 Mar 2018
PMID: 29311118
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Purpose: The retinoblastoma tumor suppressor (RB), a key regulator of cell-cycle progression and proliferation, is functionally suppressed in up to 50% of nonsmall cell lung cancer (NSCLC). RB function is exquisitely controlled by a series of proteins, including the CyclinD-CDK4/6 complex. In this study, we interrogated the capacity of a CDK4/6 inhibitor, palbociclib, to activate RB function.
Experimental Design and Results: We employed multiple isogenic RB-proficient and -deficient NSCLC lines to interrogate the cytostatic and cytotoxic capacity of CDK 4/6 inhibition in vitro and in vivo. We demonstrate that while short-term exposure to palbociclib induces cellular senescence, prolonged exposure results in inhibition of tumor growth. Mechanistically, CDK 4/6 inhibition induces a proapoptotic transcriptional program through suppression of IAPs FOXM1 and Survivin, while simultaneously augmenting expression of SMAC and caspase-3 in an RB-dependent manner.
Conclusions: This study uncovers a novel function of RB activation to induce cellular apoptosis through therapeutic administration of a palbociclib and provides a rationale for the clinical evaluation of CDK 4/6 inhibitors in the treatment of patients with NSCLC. 2018 AACR.
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Details
- Title
- Therapeutic Challenge with a CDK 4/6 Inhibitor Induces an RB-Dependent SMAC-Mediated Apoptotic Response in Non-Small Cell Lung Cancer
- Creators
- Chellappagounder Thangavel - Thomas Jefferson UniversityEttickan Boopathi - Thomas Jefferson UniversityYi Liu - Thomas Jefferson UniversityChristopher McNair - Thomas Jefferson UniversityAlex Haber - Thomas Jefferson UniversityMaryna Perepelyuk - Thomas Jefferson UniversityAnshul Bhardwaj - Thomas Jefferson UniversitySankar Addya - Thomas Jefferson UniversityAdam Ertel - Thomas Jefferson UniversitySunday Shoyele - Thomas Jefferson UniversityRuth Birbe - Thomas Jefferson UniversityJoseph M. Salvino - The Wistar InstituteAdam P. Dicker - Thomas Jefferson UniversityKaren E. Knudsen - Thomas Jefferson UniversityRobert B. Den - Thomas Jefferson University
- Publication Details
- Clinical cancer research, v 24(6), pp 1402-1414
- Publisher
- Amer Assoc Cancer Research
- Number of pages
- 13
- Grant note
- R01 DK100483 / PCF Challenge Award R01 CA099996 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA PC101841 / Department of Defense; United States Department of Defense IRG 08-060-04 / American Cancer Society P30CA010815 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) Prostate Cancer Foundation R01DK100483 / NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) PA Cure Award
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- School of Biomedical Engineering, Science, and Health Systems
- Web of Science ID
- WOS:000427627400018
- Scopus ID
- 2-s2.0-85048128550
- Other Identifier
- 991019176646404721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Oncology