Modulation of the Estrogen/erbB2 Receptors Cross-talk by CDK4/6 Inhibition Triggers Sustained Senescence in Estrogen Receptor- and ErbB2-positive Breast Cancer

被引:22
作者
Vigano, Lucia [1 ]
Locatelli, Alberta [1 ]
Ulisse, Adele [1 ]
Galbardi, Barbara [1 ]
Dugo, Matteo [1 ]
Tosi, Diego [2 ]
Tacchetti, Carlo [3 ]
Daniele, Tiziana [3 ]
Gyorffy, Balazs [4 ,5 ,6 ]
Sica, Lorenzo [1 ]
Macchini, Marina [1 ]
Zambetti, Milvia [1 ]
Zambelli, Stefania [1 ]
Bianchini, Giampaolo [1 ]
Gianni, Luca [7 ]
机构
[1] IRCCS San Raffaele Sci Inst, Dept Med Oncol, Via Olgettina 60, I-20132 Milan, Italy
[2] Inst Reg Canc Montpellier ICM Montpellier, Montpellier, France
[3] IRCCS San Raffaele Sci Inst, Expt Imaging Ctr, Milan, Italy
[4] Semmelweis Univ, Fac Gen Med, Dept Bioinformat, Budapest, Hungary
[5] Semmelweis Univ, Dept Pediat 2, Fac Med, Budapest, Hungary
[6] Inst Enzymol, TTK Oncol Biomarker Res Grp, Budapest, Hungary
[7] Fdn Michelangelo, Via Agostino Bertani 14, I-20121 Milan, Italy
关键词
KINASE; 4/6; INHIBITOR; ENDOCRINE THERAPY; ACQUIRED-RESISTANCE; PLUS PALBOCICLIB; OPEN-LABEL; FULVESTRANT; MULTICENTER; COMBINATION; EXPRESSION; MECHANISM;
D O I
10.1158/1078-0432.CCR-21-3185
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose: The interplay between estrogen receptor (ER) and erbB tyrosine-kinase receptors (RTK) impacts growth and progression of erates mitogenic signals converging onto the Cyclin-D1/CDK4/6 complex. We probed this cross-talk combining endocrine-therapy (fulvestrant), dual HER2-blockade (trastuzumab and pertuzumab), and CDK4/6-inhibition (palbociclib; PFHPert). Experimental Design: Cytotoxic drug effects, interactions, and pharmacodynamics were studied after 72 hours of treatment and over 6 more days of culture after drug wash-out in three ER+/HER2(+), two HER2(low), and two ER-negative (ER-)/HER2(+) breast cancer cell lines. We assessed gene-expression dynamic and association with Ki67 downregulation in 28 patients with ER+/HER2(+) breast cancer treated with neoadjuvant PFHPert in NA-PHER2 trial (NCT02530424). Results: In vitro, palbociclib and/or fulvestrant induced a functional activation of RTKs signalling. PFHPert had additive or synergistic antiproliferative activity, interfered with resistance mechanisms linked to the RTKs/Akt/MTORC1 axis and induced sustained senescence. Unexpected synergism was found in HER2(low) cells. In patients, Ki67 downregulation at week 2 and surgery were significantly associated to upregulation of senescence-related genes (P = 7.7E-4 and P = 1.8E-4, respectively). Activation of MTORC1 pathway was associated with high Ki67 at surgery (P = 0.019). Conclusions: Resistance associated with the combination of drugs targeting ER and HER2 can be bypassed by cotargeting Rb, enhancing transition from quiescence to sustained senescence. MTORC1 pathway activation is a potential mechanism of escape and RTKs functional activation may be an alternative pathway for survival also in ER+/HER2(low) tumor. PFHPert combination is an effective chemotherapy-free regimen for ER+/HER2(+) breast cancer, and the mechanistic elucidation of sensitivity/resistance patterns may provide insights for further treatment refinement.
引用
收藏
页码:2167 / 2179
页数:13
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