Xiuzhi Zhu1,2,3, Li Chen2,3, Binhao Huang1,4, Xiaoguang Li2,3, Liu Yang2,3, Xin Hu2,3,5, Yizhou Jiang2,3, Zhimin Shao2,3,6, Zhonghua Wang7. 1. Department of Oncology, Shanghai Medical College, Fudan University, 130 Dong-An Road, Shanghai, 200032, People's Republic of China. 2. Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, People's Republic of China. 3. Department of Breast Surgery, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, People's Republic of China. 4. Department of Gastric Surgery, Fudan University Shanghai Cancer Center, 270 Dong-An Road, Shanghai, 200032, People's Republic of China. 5. Precision Cancer Medicine Center, Shanghai, 200032, China. 6. Institutes of Biomedical Science, Fudan University, Shanghai, 200032, China. 7. Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. zhonghuawang95@hotmail.com.
Abstract
BACKGROUND: PARP inhibitors (PARPi) benefit only a fraction of breast cancer patients with BRCA mutations, and their efficacy is even more limited in triple-negative breast cancer (TNBC) due to clinical primary and acquired resistance. Here, we found that the efficacy of the PARPi olaparib in TNBC can be improved by combination with the CDK4/6 inhibitor (CDK4/6i) palbociclib. METHODS: We screened primary olaparib-sensitive and olaparib-resistant cell lines from existing BRCAmut/TNBC cell lines and generated cells with acquired olaparib resistance by gradually increasing the concentration. The effects of the PARPi olaparib and the CDK4/6i palbociclib on BRCAmut/TNBC cell lines were examined in both sensitive and resistant cells in vitro and in vivo. Pathway and gene alterations were assessed mechanistically and pharmacologically. RESULTS: We demonstrated for the first time that the combination of olaparib and palbociclib has synergistic effects against BRCAmut/TNBC both in vitro and in vivo. In olaparib-sensitive MDA-MB-436 cells, the single agent olaparib significantly inhibited cell viability and affected cell growth due to severe DNA damage. In olaparib-resistant HCC1937 and SUM149 cells, single-agent olaparib was ineffective due to potential homologous recombination (HR) repair, and the combination of olaparib and palbociclib greatly inhibited HR during the G2 phase, increased DNA damage and inhibited tumour growth. Inadequate DNA damage caused by olaparib activated the Wnt signalling pathway and upregulated MYC. Further experiments indicated that the overexpression of β-catenin, especially its hyperphosphorylation at the Ser675 site, activated the Wnt signalling pathway and mediated olaparib resistance, which could be strongly inhibited by combined treatment with palbociclib. CONCLUSIONS: Our data provide a rationale for clinical evaluation of the therapeutic synergy of the PARPi olaparib and CDK4/6i palbociclib in BRCAmut/TNBCs with high Wnt signalling activation and high MYC expression that do not respond to PARPi monotherapy.
BACKGROUND:PARP inhibitors (PARPi) benefit only a fraction of breast cancerpatients with BRCA mutations, and their efficacy is even more limited in triple-negative breast cancer (TNBC) due to clinical primary and acquired resistance. Here, we found that the efficacy of the PARPi olaparib in TNBC can be improved by combination with the CDK4/6 inhibitor (CDK4/6i) palbociclib. METHODS: We screened primary olaparib-sensitive and olaparib-resistant cell lines from existing BRCAmut/TNBC cell lines and generated cells with acquired olaparib resistance by gradually increasing the concentration. The effects of the PARPi olaparib and the CDK4/6ipalbociclib on BRCAmut/TNBC cell lines were examined in both sensitive and resistant cells in vitro and in vivo. Pathway and gene alterations were assessed mechanistically and pharmacologically. RESULTS: We demonstrated for the first time that the combination of olaparib and palbociclib has synergistic effects against BRCAmut/TNBC both in vitro and in vivo. In olaparib-sensitive MDA-MB-436 cells, the single agent olaparib significantly inhibited cell viability and affected cell growth due to severe DNA damage. In olaparib-resistant HCC1937 and SUM149 cells, single-agent olaparib was ineffective due to potential homologous recombination (HR) repair, and the combination of olaparib and palbociclib greatly inhibited HR during the G2 phase, increased DNA damage and inhibited tumour growth. Inadequate DNA damage caused by olaparib activated the Wnt signalling pathway and upregulated MYC. Further experiments indicated that the overexpression of β-catenin, especially its hyperphosphorylation at the Ser675 site, activated the Wnt signalling pathway and mediated olaparib resistance, which could be strongly inhibited by combined treatment with palbociclib. CONCLUSIONS: Our data provide a rationale for clinical evaluation of the therapeutic synergy of the PARPi olaparib and CDK4/6ipalbociclib in BRCAmut/TNBCs with high Wnt signalling activation and high MYCexpression that do not respond to PARPi monotherapy.
Authors: Rachel Greenup; Adam Buchanan; Wendy Lorizio; Keelia Rhoads; Salina Chan; Tracey Leedom; Robin King; Jane McLennan; Beth Crawford; P Kelly Marcom; E Shelley Hwang Journal: Ann Surg Oncol Date: 2013-08-22 Impact factor: 5.344
Authors: J Mateo; C J Lord; V Serra; A Tutt; J Balmaña; M Castroviejo-Bermejo; C Cruz; A Oaknin; S B Kaye; J S de Bono Journal: Ann Oncol Date: 2019-09-01 Impact factor: 32.976
Authors: Hannah Farmer; Nuala McCabe; Christopher J Lord; Andrew N J Tutt; Damian A Johnson; Tobias B Richardson; Manuela Santarosa; Krystyna J Dillon; Ian Hickson; Charlotte Knights; Niall M B Martin; Stephen P Jackson; Graeme C M Smith; Alan Ashworth Journal: Nature Date: 2005-04-14 Impact factor: 69.504