Extracellular signal-regulated kinase (ERK5) is an essential regulator of cancer progression, tumor relapse, and poor patient survival. Epithelial to mesenchymal transition (EMT) is a complex oncogenic process, which drives cell invasion, stemness, and metastases. Activators of ERK5, including mitogen-activated protein kinase 5 (MEK5), tumor necrosis factor α (TNF-α), and transforming growth factor-β (TGF-β), are known to induce EMT and metastases in breast, lung, colorectal, and other cancers. Several downstream targets of the ERK5 pathway, such as myocyte-specific enhancer factor 2c (MEF2C), activator protein-1 (AP-1), focal adhesion kinase (FAK), and c-Myc, play a critical role in the regulation of EMT transcription factors SNAIL, SLUG, and β-catenin. Moreover, ERK5 activation increases the release of extracellular matrix metalloproteinases (MMPs), facilitating breakdown of the extracellular matrix (ECM) and local tumor invasion. Targeting the ERK5 signaling pathway using small molecule inhibitors, microRNAs, and knockdown approaches decreases EMT, cell invasion, and metastases via several mechanisms. The focus of the current review is to highlight the mechanisms which are known to mediate cancer EMT via ERK5 signaling. Several therapeutic approaches that can be undertaken to target the ERK5 pathway and inhibit or reverse EMT and metastases are discussed.

Triple‐negative breast cancer (TNBC) presents a clinical challenge due to the aggressive nature of the disease and a lack of targeted therapies. Constitutive activation of the mitogen‐activated protein kinase (MAPK)/extracellular signal‐regulated kinase (ERK) pathway has been linked to chemoresistance and metastatic progression through distinct mechanisms, including activation of epithelial‐to‐mesenchymal transition (EMT) when cells adopt a motile and invasive phenotype through loss of epithelial markers (CDH1), and acquisition of mesenchymal markers (VIM, CDH2). Although MAPK/ERK1/2 kinase inhibitors (MEKi) are useful antitumor agents in a clinical setting, including the Food and Drug Administration (FDA)‐approved MEK1,2 dual inhibitors cobimetinib and trametinib, there are limitations to their clinical utility, primarily adaptation of the BRAF pathway and ocular toxicities. The MEK5 (HGNC: MAP2K5) pathway has important roles in metastatic progression of various cancer types, including those of the prostate, colon, bone and breast, and elevated levels of ERK5 expression in breast carcinomas are linked to a worse prognoses in TNBC patients. The purpose of this study is to explore MEK5 regulation of the EMT axis and to evaluate a novel pan‐MEK inhibitor on clinically aggressive TNBC cells. Our results show a distinction between the MEK1/2 and MEK5 cascades in maintenance of the mesenchymal phenotype, suggesting that the MEK5 pathway may be necessary and sufficient in EMT regulation while MEK1/2 signaling further sustains the mesenchymal state of TNBC cells. Furthermore, additive effects on MET induction are evident through the inhibition of both MEK1/2 and MEK5. Taken together, these data demonstrate the need for a better understanding of the individual roles of MEK1/2 and MEK5 signaling in breast cancer and provide a rationale for the combined targeting of these pathways to circumvent compensatory signaling and subsequent therapeutic resistance.

For the last 10 years pharmaceutical research and industry has elucidated several innovations and practices in pharmaceutical nanotechnology. Due to the increasing use of nanoparticles, the risk of human exposure rapidly increases and reliable toxicity test systems are urgently needed. Nanotoxicology refers to the study of the interactions of nanostructures with biological systems with an emphasis on the relationship between the physical and chemical properties of nanostructures with induction of toxic biological responses. It involves their unique biodistribution, clearance, accumulation, immune response and metabolism. An understanding of the relationship between the physical and chemical properties of the nanostructure and their in-vivo behavior would provide a basis for assessing toxic response and more importantly could lead to better predictive models for assessing toxicity. The current regulations for nanoparticles containing products are still in a nascent stage. The advantages of nanoparticles led to failures in noticing the toxic outcomes in living organisms. Major changes are required by considering several factors including environmental, health and safety issues. The rapid commercialization of nanotechnology requires thoughtful open discussion of broader societal impacts and urgent toxicological oversight action.

Triple negative breast cancer is characterized by the loss of hormone receptors and lack of targeted therapy. Most invasive cancers, including triple negative (TNBC) breast cancer have a mesenchymal phenotype, which is associated with increased chemoresistance. Activation of the MEK1/2 and MEK5 pathways plays a crucial role in the activation of the epithelial to mesenchymal transition program and increases the survival, proliferation, and migration of the cancer cells. Disruption of actin skeleton via ras and src mediated activation of extracellular regulated kinase 1/2 (ERK1/2) and ERK5 is reported, indicating their role in oncogenic transformation. Moreover, inhibition of either pathway results in a compensatory increase in the PI3K/AKT pathway. These crosstalk mechanisms are involved in mediating therapeutic drug resistance. MDA-MB-231, a BRAF and KRAS mutant TNBC cell line has more than 90% of high CD44+/CD24-/low stem cell population, and high ERK5 and ERK1/2 expression; hence it was used as the model for our experiments. Moreover, MDA-MB-231-ERK5-KO cells were utilized to confirm the mechanism of action. To target TNBC, known inhibitors of the MEK1/2 pathway: trametinib, an FDA approved drug for BRAF mutant melanoma, VX-11-e, an ERK2 inhibitor, and XMD-8-92, an ERK5 inhibitor were used in combination with the chemotherapeutic drugs paclitaxel and doxorubicin to examine cell viability. We have shown that dual inhibition of the ERK5 and AKT signaling pathways synergistically reduces TNBC cell viability and enhances sensitivity of the cells to paclitaxel. A series of novel quinazoline derivatives was generated to dually target the ERK5 and the AKT pathway. The effect of novel quinazolines on cell viability in combination with the chemotherapeutic agent paclitaxel was examined in the TNBC cells and some encouraging results were obtained. The overall significance of this research is to enhance the anti-cancer activity of chemotherapeutic agents and reduce off-target toxicity by dose-reduction strategy. Citation Format: Akshita B. Bhatt, Thomas D. Wright, Saloni Patel, Suravi Chakrabarty, Van Barnes, Matthew Burow, Patrick T. Flaherty, Jane Cavanaugh. Inhibition of the MAPK pathways enhances the sensitivity of triple negative breast cancer cells to chemotherapeutic drugs [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr B078. doi:10.1158/1535-7163.TARG-19-B078

: Quinoline and isoquinoline motifs are commonly encountered in natural products of diverse origins. These moderately basic fused-heterocyclic rings containing natural products are adorned with remarkable biological activities with clinical use in various diseases demonstrating nature elegance and creativity. Therefore, these privileged rings have attracted profound interest from the scientific community. In this review, we have discussed medicinal chemistry perspective of the natural products containing quinoline and isoquinoline scaffolds.