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H. Liu
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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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P2.04-019 - PD 0332991 Inhibits the Growth of Gefitinib-Resistant Human Lung Cancer Cells in Vitro and in Vivo, When Combined with Gefitinib (ID 2778)
09:30 - 09:30 | Author(s): H. Liu
- Abstract
Background:
Tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, which target the EGFR pathway, have a dramatic effect in the treatment of NSCLC patients, especially for patients with EGFR mutations, which is the leading cause of cancer-related mortality. Unfortunately, despite the success of these drugs, almost all cases progress, and eventually become resistant to such treatment, known as acquired resistance, and current targeted therapeutic strategies for patients with acquired resistance are limited. PD 0332991 is an orally active, highly selective inhibitor of the cyclin D kinases CDK4 and CDK6, with the ability to block retinoblastoma (Rb) phosphorylation.
Methods:
In this study, we evaluated, both in vitro and in vivo, the therapeutic approach of targeting the CDK4/6 and Rb pathway in PC-9/AB2 cells, which is an EGFR-TKIs acquired resistant lung adenocarcinoma cells.
Results:
PD 0332991 inhibits the growth and proliferation of both gefitinib-sensitive and gefitinib-resistant lung adenocarcinoma cells. In addition, PD 0332991 inhibits Rb phosphorylation in sensitive and resistant cell lines, as well as enhancing apoptosis in lung adenocarcinoma cells, when combined with gefitinib. The combination of PD 0332991 plus gefitinib induced G1 phase arrest for both gefitinib-sensitive and gefitinib-resistant lung cancer cells. This combination treatment also inhibited the growth and relapse of tumors in human PC-9/AB2 tumor xenograft mice, as well as inhibiting proliferation, and induced apoptosis in human PC-9/AB2 tumor xenograft mice. Treatment with PD 0332991 and gefitinib also inhibited angiogenesis in human PC-9/AB2 tumor xenograft mice.
Conclusion:
These findings provide the rationale for evaluating PD 0332991 combined with gefitinib for a novel therapeutic approach for overcoming acquired resistance to gefitinib in lung cancer.
