| Added by | celine.gongora |
|---|---|
| Group name | EquipeCG |
| Item Type | Journal Article |
| Title | Modulation of the Estrogen/erbB2 Receptors Cross-talk by CDK4/6 Inhibition Triggers Sustained Senescence in Estrogen Receptor- and ErbB2-positive Breast Cancer |
| Creator | Viganň et al. |
| Author | Lucia Viganň |
| Author | Alberta Locatelli |
| Author | Adele Ulisse |
| Author | Barbara Galbardi |
| Author | Matteo Dugo |
| Author | Diego Tosi |
| Author | Carlo Tacchetti |
| Author | Tiziana Daniele |
| Author | Balázs Gy?rffy |
| Author | Lorenzo Sica |
| Author | Marina Macchini |
| Author | Milvia Zambetti |
| Author | Stefania Zambelli |
| Author | Giampaolo Bianchini |
| Author | Luca Gianni |
| Abstract | PURPOSE: The interplay between estrogen receptor (ER) and erbB tyrosine-kinase receptors (RTK) impacts growth and progression of ER-positive (ER+)/HER2-positive (HER2+) breast cancer and generates 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 HER2low, 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 HER2low 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+/HER2low 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. |
| Publication | Clinical Cancer Research: An Official Journal of the American Association for Cancer Research |
| Volume | 28 |
| Issue | 10 |
| Pages | 2167-2179 |
| Date | 2022-05-13 |
| Journal Abbr | Clin Cancer Res |
| Language | eng |
| DOI | 10.1158/1078-0432.CCR-21-3185 |
| ISSN | 1557-3265 |
| Library Catalog | PubMed |
| Extra | PMID: 35254385 |
| Tags | Antineoplastic Combined Chemotherapy Protocols, Breast Neoplasms, Cell Line, Tumor, Cyclin-Dependent Kinase 4, Drug Resistance, Neoplasm, Estrogens, Female, Fulvestrant, Humans, Ki-67 Antigen, Mechanistic Target of Rapamycin Complex 1, original, Receptor, ErbB-2, Receptors, Estrogen |
| Date Added | 2022/08/29 - 15:34:16 |
| Date Modified | 2022/08/29 - 16:39:27 |
| Notes and Attachments | PubMed entry (Attachment) |
Institut de Recherche en Cancérologie de
