In:
Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. e17537-e17537
Abstract:
e17537 Background: Extensive-stage small cell lung cancer (SCLC) is an aggressive and lethal tumor. Despite its exquisite chemosensitivity, median survival is only 9-11 months. Topotecan is the only approved drug for relapsed SCLC and new treatments with demonstrated antitumor activity are urgently needed. Defects in PTEN and PI3KCA are common to SCLC (identified in 10-15% of tumor specimens), suggesting that inhibitors of the PI3K/AKT pathway should be evaluated. MK-2206 is a first- in-class oral allosteric AKT inhibitor that is both potent and highly selective against all AKT isoforms. Our aim is to determine if MK-2206 plus topotecan has superior anticancer activity compared to either agent alone in SCLC cell lines. Methods: Three SCLC cell lines (H526- PTEN/PI3K wild type; H69- PTEN wild type/PI3K mutated; H2196- PTEN mutated/PI3K wild type) were treated with MK2206, topotecan or the combination. Median Effect Analysis was conducted using proliferation assays to test the combination for synergy. Immunoblotting was performed to explore the targeted effect on the PI3K/AKT pathway while flow cytometry was used to determine cell cycle effects. Results: H526 cells were refractory to selective AKT inhibition, but sensitive to topotecan. In contrast, H69 cells were responsive to single-agent MK2206, but two orders of magnitude less sensitive to topotecan. The H2196 cell line was sensitive to both agents. All cell lines showed decreased phosphoAKT (S473) with MK2206. In the combination experiments, additive to moderately synergistic interactions were detected in all cell lines with the greatest synergism observed in the H69 cells. Increased PARP cleavage was observed in response to the combination treatment compared to single-agent topotecan suggesting that AKT inhibition improved the activity of topotecan. In H69, a prolonged G1/S-phase arrest was observed in the combination compared to single-agent treatment. Conclusions: MK2206 demonstrated antitumor activity in SCLC cell lines harboring PI3K or PTEN mutations and enhanced the activity of topotecan in wild type and mutant cell lines. Based on this data, a SWOG clinical trial of topotecan plus MK2206 versus topotecan in relapsed SCLC is in development.
Type of Medium:
Online Resource
ISSN:
0732-183X
,
1527-7755
DOI:
10.1200/jco.2012.30.15_suppl.e17537
Language:
English
Publisher:
American Society of Clinical Oncology (ASCO)
Publication Date:
2012
detail.hit.zdb_id:
2005181-5
