Purpose: The interplay between estrogen-receptor (ER) and erb-B tyrosine-kinase receptors (RTKs) impacts growth and progression of ER+/HER2+ breast cancer (BC) and generates mitogenic signals converging onto the Cyclin-D1/CDK4/6 complex. We probed this crosstalk combining endocrine-therapy (fulvestrant), dual HER2-blockade (trastuzumab and pertuzumab) and CDK4/6-inhibition (palbociclib) (PFHPert). Methods: 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-/HER2+ BC cell lines. We assessed gene-expression dynamic and association with Ki67 downregulation in 28 patients with ER+/HER2+ BC 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 week2 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 co-targeting 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+ BC and the mechanistic elucidation of sensitivity/resistance patterns may provide insights for further treatment refinement.

Modulation of the estrogen/erbB2 receptors crosstalk by CDK4/6 inhibition triggers sustained senescence in estrogen receptor and erbB2 positive breast cancer

Tacchetti, Carlo;Zambelli, Stefania;Bianchini, Giampaolo;
2022-01-01

Abstract

Purpose: The interplay between estrogen-receptor (ER) and erb-B tyrosine-kinase receptors (RTKs) impacts growth and progression of ER+/HER2+ breast cancer (BC) and generates mitogenic signals converging onto the Cyclin-D1/CDK4/6 complex. We probed this crosstalk combining endocrine-therapy (fulvestrant), dual HER2-blockade (trastuzumab and pertuzumab) and CDK4/6-inhibition (palbociclib) (PFHPert). Methods: 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-/HER2+ BC cell lines. We assessed gene-expression dynamic and association with Ki67 downregulation in 28 patients with ER+/HER2+ BC 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 week2 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 co-targeting 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+ BC and the mechanistic elucidation of sensitivity/resistance patterns may provide insights for further treatment refinement.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11768/126796
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