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L.A. Marek
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P2.04 - Poster Session/ Biology, Pathology, and Molecular Testing (ID 234)
- Event: WCLC 2015
- Type: Poster
- Track: Biology, Pathology, and Molecular Testing
- Presentations: 1
- Moderators:
- Coordinates: 9/08/2015, 09:30 - 17:00, Exhibit Hall (Hall B+C)
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P2.04-007 - In Vitro and in Vivo Efficacy of AZD9291 Is Enhanced by Combination with AZD4547 in EGFR Mutant Lung Cancer Cells (ID 2456)
09:30 - 09:30 | Author(s): L.A. Marek
- Abstract
Background:
EGFR-specific tyrosine kinase inhibitors (TKIs) provide marked clinical responses in patients bearing EGFR mutated lung tumors, although acquired resistance limits the durability of the response. In light of the frequent emergence of erlotinib and gefitinib-resistant EGFR T790M mutations upon tumor progression, 3[rd] generation EGFR-specific TKIs have been developed that specifically inhibit gain-of-function EGFR mutants irrespective of T790M status. Recently, we reported a distinct mechanism of acquired resistance whereby specific EGFR mutant lung cancer cell lines including H1650 and HCC4006 cells, but not PC9 cells, undergo an epithelial-mesenchymal transition (EMT) upon chronic in vitro treatment with gefitinib. As a result, the adapted cells acquire vulnerability to FGFR inhibitors by virtue of EMT-mediated FGF2 and FGFR1 induction. Herein, we have tested the hypothesis that combination of the FGFR inhibitor, AZD4547, with the 3[rd] generation EGFR TKI, AZD9291 will yield superior anti-tumor activity relative to AZD9291 alone.
Methods:
Lung cancer cell lines bearing gain-of-function EGFR mutations (HCC4006, H1650 and PC9) were submitted to in vitro clonogenic growth assays in the presence of AZD9291 and/or AZD4547 over concentration ranges for 1 to 300 nM for each drug. For in vivo measurement of the activity of these drugs, flank xenografts were established in Nu/Nu mice with the 3 lung cancer cell lines and treated by daily oral gavage (5 days on, 2 days off) with diluent, AZD9291 (5 mg/kg), AZD4547 (12.5 mg/kg) and the combination of the two drugs at these doses. Tumor size was measured with calipers and volume was calculated using the formula, Volume=3.14(short diameter)[2](long diameter)/6.
Results:
HCC4006, H1650 and PC9 cells were highly sensitive to ZD9291 in vitro with IC~50~ values of 1.6, 7.4 and 3.3 nM, respectively. In a 2 week clonogenic growth assay, AZD9291 reduced growth of all cell lines by >95%, although viable drug resistant persisters clearly remained. While none of these cell lines exhibited significant growth inhibition in response to AZD4547 alone, combination of AZD9291 and AZD4547 further reduced clonogenic growth of HCC4006 and H1650 cells, but not PC9 cells. In flank xenograft studies, AZD9291 monotherapy induced marked tumor shrinkage (H1650, ~80% at day 10; HCC4006, ~90% at day 30; PC9, 89% at day 25), although regrowth of the tumors occurred with all three xenografts. AZD4547 yielded little or no growth inhibition as a monotherapy, but significantly enhanced the degree of tumor shrinkage and delayed the time to tumor progression in H1650 and HCC4006 tumors, but not PC9 tumors.
Conclusion:
Combination of the FGFR inhibitor AZD4547 with AZD9291 affords greater growth suppression relative to AZD9291 alone in HCC4006 and H1650 cells that undergo EMT and induction of an FGF2-FGFR1 pathway. Predictably, this combination was not more effective compared to AZD9291 alone in PC9 cells that fail to undergo EMT in response to EGFR TKI treatment. The studies support the efficacy of combined AZD9291 and AZD4547 treatment of a subset of lung tumors driven by mutated EGFR, although the features of these particular lung tumors that predict this response is unknown at this time.
