NEW THERAPIES FOR CREB3L1-DEFICIENT TRIPLE NEGATIVE BREAST CANCER

Abstract

ABSTRACT The lack of targeted therapies for triple-negative breast cancer (TNBC) contributes to their high mortality rates and high risk of relapse compared to other subtypes of breast cancer. Developing targeted therapies for TNBC is an unmet clinical need. Our lab has described metastasis suppressor cAMP-responsive element-binding protein 3- like protein 1 (CREB3L1) deficiency as a novel molecular feature of TNBCs. CREB3L1 has been shown to function as a metastasis suppressor in breast cancer, downregulating genes involved in tumorigenesis, angiogenesis, migration and invasion.

In this project, inhibitors that selectively block the growth and/or survival of metastatic CREB3L1-deficient breast cancer cells have been identified and validated as new treatments for CREB3L1-deficient breast cancers. A global drug discovery approach was used to screen 1,818 FDA-approved drugs for their ability to kill CREB3L1-deficient TNBC cells at 1μM. Of the 47 drugs identified, 27 drugs were then confirmed as killing CREB3L1-deficient TNBC cells in validation experiments. The 27 drugs were then titrated out over a range of concentrations to determine their ability to selectively kill CREB3L1-deficient TNBC cells at concentrations lower than 1 μM.

Four compounds, palbociclib isethionate, cladribine, isolanid and homoharringtonine, were validated as selectively killing CREB3L1-deficient TNBC cells significantly more than CREB3L1 re-expressing cells at concentrations lower than 1 μM. The majority of these drugs also killed nontumorigenic control normal breast cells (MCF10A cells) at these same concentrations, with the exception of cladribine. Importantly, three of the four promising drugs identified, with the exception of isolanid, displayed synergistic interactions when combined with standard of care chemotherapeutic reagent doxorubicin, reducing the dose required to achieve the desired cytotoxic response. Furthermore, the selective CREB3L1-deficient effects of these compounds were exhibited across multiple CREB3L1-deficient TNBC cell lines, suggesting they may be broadly applicable for the treatment of TNBCs.

The top four compounds identified in this project show promise as more selective therapies for CREB3L1-deficient TNBC and their further evaluation in vivo and possible future clinical implementation would address the unmet clinical need of designing targeted therapies for TNBC.