PI3K Inhibition Impairs BRCA1/2 Expression and Sensitizes BRCA-Proficient Triple-Negative Breast Cancer to PARP Inhibition
Yasir H. Ibrahim,Celina Garcia-Garcia,Violeta Serra,Lei He,Kristine Torres-Lockhart,Aleix Prat,Pilar Anton,Patricia Cozar,Marta Guzman,Judit Grueso,Olga Graciela Cantu Rodriguez,Maria Teresa Calvo,Claudia Aura,Orland Diez,Isabel T. Rubio,José Francisco Pérez,Jordi Rodon,Javier Cortes,Leif W. Ellisen,Maurizio Scaltriti,José Baselga +20 more
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TLDR
It is shown thatPI3K blockade results in HR impairment and sensitization to PARP inhibition in TNBCs without BRCA mutations, providing a rationale to combine PI3K and PARP inhibitors in this indication.Abstract:
PARP inhibitors are active in tumors with defects in DNA homologous recombination (HR) due to BRCA1/2 mutations. The phosphoinositide 3-kinase (PI3K) signaling pathway preserves HR steady state. We hypothesized that in BRCA-proficient triple-negative breast cancer (TNBC), PI3K inhibition would result in HR impairment and subsequent sensitization to PARP inhibitors. We show in TNBC cells that PI3K inhibition leads to DNA damage, downregulation of BRCA1/2, gain in poly-ADP-ribosylation, and subsequent sensitization to PARP inhibition. In TNBC patient–derived primary tumor xenografts, dual PI3K and PARP inhibition with BKM120 and olaparib reduced the growth of tumors displaying BRCA1/2 downregulation following PI3K inhibition. PI3K-mediated BRCA downregulation was accompanied by extracellular signal–regulated kinase (ERK) phosphorylation. Overexpression of an active form of MEK1 resulted in ERK activation and downregulation of BRCA1, whereas the MEK inhibitor AZD6244 increased BRCA1/2 expression and reversed the effects of MEK1. We subsequently identified that the ETS1 transcription factor was involved in the ERK-dependent BRCA1/2 downregulation and that knockdown of ETS1 led to increased BRCA1/2 expression, limiting the sensitivity to combined BKM120 and olaparib in 3-dimensional culture. Significance: Treatment options are limited for patients with TNBCs. PARP inhibitors have clinical activity restricted to a small subgroup of patients with BRCA mutations. Here, we show that PI3K blockade results in HR impairment and sensitization to PARP inhibition in TNBCs without BRCA mutations, providing a rationale to combine PI3K and PARP inhibitors in this indication. Our findings could greatly expand the number of patients with breast cancer that would benefit from therapy with PARP inhibitors. On the basis of our findings, a clinical trial with BKM120 and olaparib is being initiated in patients with TNBCs. Cancer Discov; 2(11); 1036–47. ©2012 AACR . Read the Commentary on this article by Rehman et al., p. 982. This article is highlighted in the In This Issue feature, p. 961read more
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Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013
A. Goldhirsch,E P Winer,A S Coates,R. D. Gelber,M Piccart-Gebhart,B. Thürlimann,H.-J. Senn,Kathy S. Albain,Fabrice Andre,Jonas Bergh,Hervé Bonnefoi,Denisse Bretel-Morales,Harold J. Burstein,Fatima Cardoso,M. Castiglione-Gertsch,Alan S. Coates,Marco Colleoni,Alberto Costa,Giuseppe Curigliano,Nancy E. Davidson,Angelo Di Leo,Bent Ejlertsen,John F. Forbes,Richard D. Gelber,Michael Gnant,Aron Goldhirsch,Pamela J. Goodwin,Paul E. Goss,Jay R. Harris,Daniel F. Hayes,Clifford A. Hudis,James N. Ingle,Jacek Jassem,Zefei Jiang,Per Karlsson,Sibylle Loibl,Monica Morrow,Moïse Namer,C. Kent Osborne,Ann H. Partridge,Frédérique Penault-Llorca,Charles M. Perou,Martine Piccart-Gebhart,Kathleen I. Pritchard,Emiel J. Th. Rutgers,Felix Sedlmayer,Vladimir Semiglazov,Z Shao,Ian E. Smith,Beat Thürlimann,Masakazu Toi,Andrew Tutt,Michael Untch,Giuseppe Viale,Toru Watanabe,Nicholas Wilcken,Eric P. Winer,William C. Wood +57 more
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