期刊
CLINICAL CANCER RESEARCH
卷 28, 期 10, 页码 2167-2179出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-21-3185
关键词
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类别
资金
- BCRF [18-181]
- Associazione Italiana per la Ricerca sul Cancro (AIRC) [21787, IG 2018]
- Higher Education Institutional Excellence Programme of the Ministry for Innovation and Technology in Hungary [2020-4.1.1.-TKP2020]
- Pfizer Italia S.r.l.
- Roche
This study investigates the interplay between ER and HER2 and its impact on the growth and progression of ER-positive breast cancer. It finds that combination therapy can bypass resistance mechanisms and that RTK functional activation may be an alternative survival pathway in ER+/HER2(low) tumors.
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.
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