Abstract 1879: Novel diphenylamine analogs induce mesenchymal to epithelial transition and enhance the sensitivity of breast cancer cells to conventional chemotherapeutic agents
Authors: Bhatt Akshita B. , Wright Thomas D. , Anna Katie , Gupta Mohit , Chakrabarty Suravi , Hoang Van , Burow Matthew , Flaherty Patrick T. , Cavanaugh Jane E. 
Published: August 2019

Epithelial to mesenchymal transition is an important cellular adaptation that helps cancer cells acquire a spindle-like phenotype from a cuboidal phenotype, degrade the extracellular matrix, invade the neighboring tissues, and metastasize to other organs and form secondary tumor. Cellular plasticity is governed by growth factors that act in a paracrine manner to activate downstream oncogenes and regulate the activity of epigenetic factors, which facilitate phenotypic switch from epithelial to mesenchymal, ultimately leading to increased cell migration and invasion. The intracellular phosphorylation cascade that is downstream of growth factor receptors plays an important role in transmitting the signal from the extracellular environment into the nucleus, thereby completing the loop required to elicit a cellular response. Triple negative breast cancer (TNBC), characterized by loss of hormone receptors is a highly aggressive form of cancer and patients show poor prognosis and disease-free survival due to lack of targeted therapy. In contrast, estrogen positive breast cancer can be targeted by estrogen receptor antagonists or CDK4/6 inhibitors, but drug resistance and relapse is often associated with epithelial to mesenchymal transition and poor patient outcome. Hence, targeting the mesenchymal phenotype with small molecule inhibitors is an emerging strategy to attenuate the invasive and aggressive nature of cancer cells. The MEK5-ERK5 pathway is understudied in triple negative breast cancer and there are few research tools available to selectively inhibit this pathway. Diphenylamine derivatives, synthesized as putative MEK5 inhibitors from parent MEK1/2 inhibitor trametinib, are effective in inducing mesenchymal to epithelial transition in MDA-MB-231 triple negative breast cancer cells, as indicated by an increase in E-cadherin expression, which is a marker of epithelial phenotype, and a decrease in spindle index, an important cell shape determinant. Compound 1, a dual MEK1/2 (98%) and MEK5 (59%) inhibitor was further characterized in functional assays; Compound 1 was found to significantly inhibit cell viability, proliferation, migration, spheroid viability, and colony formation in MDA-MB-231 cells. Compound 1 is effective in reversing the mesenchymal phenotype of MDA-MB-231, BT-549, and tamoxifen resistant-MCF-7 breast cancer cells. Signaling crosstalk and drug resistance in cancer limits the applicability of monotherapy. Our current work is focused on treating diverse breast cancer cells with combination of novel compound 1 and paclitaxel, ipatasertib, JQ-1, and LBH589 to induce synthetic lethality at lower concentration, restore drug sensitivity, and enhance selectivity.

Citation Format: Akshita B. Bhatt, Thomas D. Wright, Katie Anna, Mohit Gupta, Suravi Chakrabarty, Van Hoang, Matthew Burow, Patrick T. Flaherty, Jane E. Cavanaugh. Novel diphenylamine analogs induce mesenchymal to epithelial transition and enhance the sensitivity of breast cancer cells to conventional chemotherapeutic agents [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1879.