For a study, researchers sought to investigate the interaction of the estrogen receptor (ER) and the erbB tyrosine kinase receptors (RTK) using a combination of endocrine therapy (fulvestrant), dual HER2-blockade (trastuzumab and pertuzumab), and CDK4/6 inhibition (palbociclib; PFHPert). Cytotoxic drug effects, interactions, and pharmacodynamics were investigated in 3 ER+/HER2+, 2 HER2low, and 2 ER-negative (ER−)/HER2+ breast cancer cell lines after 72 hours of treatment and 6 additional days of culture after drug wash-out. In the NA-PHER2 trial, investigators looked at gene expression dynamics and their relationship to Ki67 downregulation in 28 patients with ER+/HER2+ breast cancer given neoadjuvant PFHPert (NCT02530424). Palbociclib and fulvestrant induced functional activation of RTK signaling in vitro. PFHPert inhibited resistance mechanisms linked to the RTKs/Akt/MTORC1 axis, induced sustained senescence, and had additive or synergistic antiproliferative activity. In HER2low cells, an unexpected synergism was discovered. Ki67 downregulation at week 2 and surgery was associated with upregulation of senescence-related genes in patients (P=7.7E-4 and P=1.8E-4, respectively). MTORC1 pathway activation was associated with high Ki67 at surgery (P=0.019). Resistance caused by ER and HER2 drugs can be avoided by co-targeting Rb, accelerating the transition from quiescence to sustained senescence. MTORC1 pathway activation was a potential escape mechanism, and RTK functional activation may be an alternative survival pathway in ER+/HER2low tumors. The PFHPert combination was a chemotherapy-free regimen that was effective for ER+/HER2+ breast cancer, and the mechanistic elucidation of sensitivity/resistance patterns may provide insights for future treatment refinement.