The combination of the PARP inhibitor Olaparib and the WEE1 inhibitor AZD1775 as a new therapeutic option for small cell lung cancer

Lallo, A. et al. (2018) The combination of the PARP inhibitor Olaparib and the WEE1 inhibitor AZD1775 as a new therapeutic option for small cell lung cancer. Clinical Cancer Research, 24(20), pp. 5153-5164. (doi: 10.1158/1078-0432.CCR-17-2805) (PMID:29941481)

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Abstract

Purpose: Introduced in 1987, platinum-based chemotherapy remains standard of care for small cell lung cancer (SCLC), a most aggressive, recalcitrant tumor. Prominent barriers to progress are paucity of tumor tissue to identify drug targets and patient-relevant models to interrogate novel therapies. Following our development of circulating tumor cell patient–derived explants (CDX) as models that faithfully mirror patient disease, here we exploit CDX to examine new therapeutic options for SCLC. Experimental Design: We investigated the efficacy of the PARP inhibitor olaparib alone or in combination with the WEE1 kinase inhibitor AZD1775 in 10 phenotypically distinct SCLC CDX in vivo and/or ex vivo. These CDX represent chemosensitive and chemorefractory disease including the first reported paired CDX generated longitudinally before treatment and upon disease progression. Results: There was a heterogeneous depth and duration of response to olaparib/AZD1775 that diminished when tested at disease progression. However, efficacy of this combination consistently exceeded that of cisplatin/etoposide, with cures in one CDX model. Genomic and protein analyses revealed defects in homologous recombination repair genes and oncogenes that induce replication stress (such as MYC family members), predisposed CDX to combined olaparib/AZD1775 sensitivity, although universal predictors of response were not noted. Conclusions: These preclinical data provide a strong rationale to trial this combination in the clinic informed by prevalent, readily accessed circulating tumor cell–based biomarkers. New therapies will be evaluated in SCLC patients after first-line chemotherapy, and our data suggest that the combination of olaparib/AZD1775 should be used as early as possible and before disease relapse.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Miller, Professor Crispin
Authors: Lallo, A., Frese, K. K., Morrow, C. J., Sloane, R., Gulati, S., Schenk, M. W., Trapani, F., Simms, N., Galvin, M., Brown, S., Hodgkinson, C. L., Priest, L., Hughes, A., Lai, Z., Cadogan, E., Khandelwal, G., Simpson, K. L., Miller, C., Blackhall, F., O'Connor, M. J., and Dive, C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Clinical Cancer Research
Publisher:American Association for Cancer Research
ISSN:1078-0432
ISSN (Online):1557-3265
Published Online:25 June 2018
Copyright Holders:Copyright © 2018 American Association for Cancer Research
First Published:First published in Clinical Cancer Research 24(20):5153-5164
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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