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The Gamma Secretase Inhibitor BMS-906024 Enhances Anti-Tumor Activity of Standard Chemotherapy in Preclinical Lung Adenocarcinoma Models

by
Katherine Morgan
B.S., Muhlenberg College - 2007

Thesis Advisor: Sharon A. Pine, Ph.D.
Graduate Program in Cellular & Molecular Pharmacology

Rutgers Cancer Institute of NJ (CINJ)
Auditorium A
New Brunswick

Monday, April 10, 2017
1:30 p.m.


Abstract

Notch signaling is aberrantly activated in approximately one third of non-small cell lung cancer (NSCLC) cases, primarily through loss of the endogenous inhibitor, Numb, or via gain-of-function mutations in the Notch1 receptor, and is associated with poor overall survival. We characterized the interaction between BMS-906024, a clinically relevant gamma secretase inhibitor (GSI) that inhibits Notch activation, and front-line chemotherapy in preclinical models of NSCLC. Chemosensitivity MTS assays consisting of treatment with BMS-906024, cisplatin or paclitaxel, or the combination of GSI and chemotherapy were performed on a panel of human NSCLC cell lines, most of which were derived from adenocarcinomas. Analysis of the drug effects with CalcuSyn yielded significantly greater synergy for the GSI BMS-906024 combined with paclitaxel than with cisplatin (average CI = 0.54 vs 0.85, respectively; P = 0.01). Additionally, MTS assays performed on an extended panel of 31 NSCLC cell lines demonstrated that the synergy between BMS-906024 and paclitaxel was significantly greater in KRAS- and BRAF-wildtype than KRAS- or BRAF-mutant cells (average CI = 0.43 vs 0.90, respectively; P=0.003), while there was no correlation with EGFR or TP53 status. Treatment of cell line- and patient-derived lung adenocarcinoma xenografts in mice confirmed enhanced anti-tumor activity for the combination of BMS-906024 and paclitaxel via decreased cell proliferation and increased apoptosis. These results are a step toward identification of the optimal combination of the GSI BMS-906024 with standard chemotherapies, as well as potential biomarkers that may predict patient response to Notch-targeted therapy.


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