Cell Signaling Analysis of Metastatic Triple Negative Breast Cancer Following Dual PI3K/mTOR Inhibitor (PIKTOR)



Nguyen, Tuong Vi V

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Triple negative breast cancer (TNBC) is defined by deficient estrogen, progesterone and HER2 receptor expression, excluding TNBC patients from effective targeted therapies for breast cancer. Advancement in targeted therapy for pro-survival pathways like PI3K/AKT/mTOR (PAM) and mitogen activated protein kinase (MAPK), has shown to improve outcomes for select TNBC patients. However, targeted therapies have not produced complete responses in the majority of patients and there is high degree of systemic relapse following conventional neoadjuvant chemotherapy, resulting in overall low therapeutic response for TNBC patients. Here we aimed to identify patterns of expression in responders vs non-responders by examining the signaling profile of metastatic (met) TNBC patients following targeted therapy against the PAM pathway. Ten patients were given an investigational oral combination of TAK-117 and TAK-228 (PIKTOR), a selective PI3Kα inhibitor and a TORC1/2 inhibitor respectively, predicted to impair DNA damage repair (DDR) pathways, increasing genomic instability and tumor sensitivity to chemotherapy. The hypothesis was successful inhibition of the PAM pathway by PIKTOR could downregulate effectors/modulator proteins of NHEJ in HRD cells. Signaling profile of pre- and post-tumor biopsy samples following PIKTOR were mapped via RPPA. Overall analysis showed heterogeneity of disease and response to treatment. The proteomic profile indicated compensatory signaling in response to treatment via upregulation of partnering MAPK pathway or upstream RTKs. Heterogenous signaling in DDR signaling pathway suggest a nonspecific stress response by TNBC tumors, unlikely to correlate DDR deficiency to patient treatment response. Pathway expression analysis of metTNBC patients at baseline and post-PIKTOR therapy highlighted key nodes in the pathway which have the potential to contribute to disease relapse. Data generated from this study could elucidate common pathway of resistance accessible for future treatments and help guide future therapeutic discoveries for advanced, metTNBC.


This thesis has been embargoed for 2 years. It will not be available until April 2023 at the earliest.


Triple negative breast cancer, PI3K/ mTOR, Phase II clinical trial, Personalized medicine, Dual inhibitor, PIKTOR