Dual MTOR Kinase Inhibitor MLN0128 Sensitizes HR/HER2 Breast Cancer Patient-Derived Xenografts to Trastuzumab or Fulvestrant

Therapeutic strategies against hormonal receptor-positive (HR)/HER2 breast cancers with poor response to trastuzumab need to be optimized. Two HR/HER2 patient-derived xenograft (PDX) models named as COH-SC1 and COH-SC31 were established to explore targeted therapies for HER2 breast cancers. RNA sequencing and RPPA (reverse phase protein array) analyses were conducted to decipher molecular features of the two PDXs and define the therapeutic strategy of interest, validated by drug efficacy examination and cell proliferation analysis. Estrogen acted as a growth driver of trastuzumab-resistant COH-SC31 tumors but an accelerator in the trastuzumab-sensitive COH-SC1 model. trastuzumab efficacy examination further confirmed the consistent responses between PDXs and the corresponding tumors. Integrative omics analysis revealed that mammalian target of rapamycin (mTOR) and ERα signaling predominantly regulate tumor growth of the two HR/HER2 PDXs. Combination of the dual mTOR complex inhibitor MLN0128 and anti-HER2 trastuzumab strongly suppressed tumor growth of COH-SC1 PDX accompanied by increasing ER-positive cell population Instead, MLN0128 in combination with antiestrogen fulvestrant significantly halted the growth of HR/HER2 cancer cells and trastuzumab-resistant COH-SC31 as well as trastuzumab-sensitive COH-SC1 tumors Compared with the standard trastuzumab treatment, this study demonstrates alternative therapeutic strategies against HR/HER2 tumors through establishment of two PDXs coupled with integrative omics analyses and drug efficacy examination. This work presents a prototype of future "co-clinical" trials to tailor personalized medicine in clinical practice. .