Korkola, J. | Search bioRxiv

bioRxiv2018

Targeting mitochondria in cancer therapy could provide a basis for the selective anti-cancer activity

To determine the target of the recently identified lead compound NSC130362 that is responsible for its selective anti-cancer efficacy and safety in normal cells, structure-activity relationship (SAR) studies were conducted. First, NSC13062 was validated as a starting compound for the described SAR studies in a variety of cell-based viability assays. Then, a small library of 1,4-naphthoquinines (1,4-NQs) and quinoline-5,8-diones was tested in cell viability assays using pancreatic cancer MIA PaCa-2 cells and normal human hepatocytes. The obtained data allowed us to select a set of both non-toxic compounds that preferentially induced apoptosis in cancer cells and toxic compounds that induced apoptosis in both cancer and normal cells. Anti-cancer activity of the selected non-toxic compounds was confirmed in viability assays using breast cancer HCC1187 cells. Consequently, the two sets of compounds were tested in multiple cell-based and in vitro activity assays to identify key factors responsible for the observed activity. Inhibition of the mitochondrial electron transfer chain (ETC) is a key distinguishing activity between the non-toxic and toxic compounds. Finally, we developed a mathematical model that was able to distinguish these two sets of compounds. The development of this model supports our conclusion that appropriate quantitative SAR (QSAR) models have the potential to be employed to develop anticancer compounds with improved potency while maintaining non-toxicity to normal cells.

cancer biology↗

bioRxiv2017

Kinome rewiring reveals AURKA is a molecular barrier to the efficacy of PI3K/mTOR-pathway inhibitors in breast cancer

Dysregulation of the PI3K-AKT-mTOR signaling network is a prominent feature of breast cancers. However, clinical responses to drugs targeting this pathway have been modest. We hypothesized that dynamic changes in signaling, including adaptation and feedback, limit drug efficacy. Using a quantitative chemoproteomics approach we mapped dynamic changes in the kinome in response to various agents and identified signaling changes that correlate with drug sensitivity. Measurement of dynamics across a panel of breast cancer cell lines identified that maintenance of CDK4 and AURKA activity was associated with drug resistance. We tested whether incomplete inhibition of CDK4 or AURKA was a source of therapy failure and found that inhibition of either was sufficient to sensitize most breast cancer cells to PI3K, AKT, and mTOR inhibitors. In particular, drug combinations including the AURKA inhibitor MLN8237 were highly synergistic and induced apoptosis through enhanced suppression of mTOR signaling to S6 and 4E-BP1 leading to tumor regression in vivo. This signaling map identifies survival factors whose presence limits the efficacy of target therapy and indicates that Aurora kinase co-inhibition could unlock the full potential of PI3K-AKT-mTOR pathway inhibitors in breast cancer.

cancer biology↗