Defense Date
3-4-2021
Graduation Date
Spring 5-22-2021
Availability
Immediate Access
Submission Type
dissertation
Degree Name
PhD
Department
Pharmacology
School
School of Pharmacy
Committee Chair
Jane E. Cavanaugh
Committee Member
Paula Witt-Enderby
Committee Member
Rehana Leak
Committee Member
Patrick T. Flaherty
Committee Member
Kevin Tidgewell
Keywords
ERK1/2, ERK5, EMT, MET, cancer, signaling
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive form of breast cancer and accounts for 10-15% of breast cancer cases. Due to absence of estrogen, progesterone, and human epidermal growth factor receptors, there is lack of targeted therapies and chemotherapy remains the mainstay treatment. Moreover, drug resistance is a major problem associated specifically with TNBC. Similarly, while estrogen receptor positive (ER+) breast cancer can be treated with targeted therapies such as tamoxifen, 40% of patients develop resistance and resulting in recurrence of the disease.
There is a dire need for identifying novel targets and developing therapeutics to target triple-negative and tamoxifen-resistant (TAMR) breast cancers. Activation of one of the newest members of mitogen-activated protein kinase (MAPK) family, extracellular-regulated kinase (ERK) 5 is known to increase cell viability, proliferation, and migration in different cancers and its overexpression correlates with poor patient survival. In breast cancer, activation of mitogen activated protein kinase kinase (MEK) 5, the upstream kinase of ERK5, and/or ERK5 promotes drug resistance, the epithelial to mesenchymal transition (EMT), and hormone independence. Once the cancer cells undergo an EMT, they are harder to target and contain, leading to metastases. Therefore, there is an urgent need to understand the pathways that drive proliferation and the EMT and develop novel therapies that target these pathways.
TNBCs are heterogeneous in their mutational profile and reliance on specific signaling pathways. Therefore, in addition to the ERK5 pathway, the ERK1/2 and phosphoinositol-3-kinase (PI3K)-AKT pathways have been shown to have overlapping and distinct functions as the ERK5 pathway to regulate tumorigenesis in TNBC and TAMR breast cancers. Interestingly, inhibition of one of these signaling pathways often leads to a compensatory increased activation of the other signaling cascades.
The main goals of this project are 1) to target the ERK1/2 and ERK5 pathways and develop strategies to reverse the EMT using novel and known pharmacological inhibitors and molecular tools and 2) determine the effect of novel and known kinase inhibitors on chemotherapeutic sensitivity and 3) determine the effect of novel compounds that target the ERK1/2 and ERK5 pathways in combination with the AKT inhibitor ipatasertib on spheroid viability, migration, and proliferation in TNBCs. The results from this study will aid in the design of innovative therapeutic strategies that target cancer metastases and reduce therapeutic resistance.
Language
English
Recommended Citation
Bhatt, A. (2021). Targeting the MEK5, MEK1/2, and/or PI3K Pathways to Reverse Epithelial to Mesenchymal Transition and Enhance Chemotherapeutic Sensitivity in Breast And Brain Cancers (Doctoral dissertation, Duquesne University). Retrieved from https://dsc.duq.edu/etd/1962
Additional Citations
1) Bhatt, A. B.; Wright, T. D.; Barnes, V.; Chakrabarty, S.; Matossian, M. D.; Lexner, E.; Ucar, D. A.; Miele, L.; Flaherty, P. T.; Burow, M. E.; Cavanaugh, J. E., Diverse and converging roles of ERK1/2 and ERK5 pathways on mesenchymal to epithelial transition in breast cancer. Translational Oncology 2021, 14 (6), 101046.
2) Bhatt AB, Patel S, Matossian MD, Ucar DA, Miele L, Burow ME, Flaherty PT, Cavanaugh JE. Molecular Mechanisms of Epithelial to Mesenchymal Transition Regulated by ERK5 Signaling. Biomolecules. 2021 Jan 29;11(2):183. doi: 10.3390/biom11020183. PMID: 33572742.
3) Bhatt AB, Gupta M, Hoang VT, Chakrabarty S, Wright TD, Elliot S, Chopra IK, Monlish D, Anna K, Burow ME, Cavanaugh JE, Flaherty PT. Novel Diphenylamine Analogs Induce Mesenchymal to Epithelial Transition in Triple Negative Breast Cancer. Front Oncol. 2019 Jul 30;9:672. doi: 10.3389/fonc.2019.00672. PMID: 31417863; PMCID: PMC6682674.
4) Wright TD, Raybuck C, Bhatt A, Monlish D, Chakrabarty S, Wendekier K, Gartland N, Gupta M, Burow ME, Flaherty PT, Cavanaugh JE. Pharmacological inhibition of the MEK5/ERK5 and PI3K/Akt signaling pathways synergistically reduces viability in triple-negative breast cancer. J Cell Biochem. 2020 Feb;121(2):1156-1168. doi: 10.1002/jcb.29350. Epub 2019 Aug 28. PMID: 31464004; PMCID: PMC6923606.
5) Hoang VT, Matossian MD, Ucar DA, Elliott S, La J, Wright MK, Burks HE, Perles A, Hossain F, King CT, Browning VE, Bursavich J, Fang F, Del Valle L, Bhatt AB, Cavanaugh JE, Flaherty PT, Anbalagan M, Rowan BG, Bratton MR, Nephew KP, Miele L, Collins-Burow BM, Martin EC, Burow ME. ERK5 Is Required for Tumor Growth and Maintenance Through Regulation of the Extracellular Matrix in Triple Negative Breast Cancer. Front Oncol. 2020 Aug 3;10:1164. doi: 10.3389/fonc.2020.01164. PMID: 32850332; PMCID: PMC7416559.
1) Bhatt AB, Anna K, Schottland S, Martin J, Wright TD, Gupta M, Matossian MD, Ucar DA, Chakrabarty S, Barnes V, Patel S, Miele L, Burow ME, Flaherty PT, Cavanaugh JE. Dual inhibition of MEK5 and MEK1/2 or PI3K pathways decreases cell viability, proliferation, migration, and stemness, and induces mesenchymal to epithelial transition in glioblastoma multiforme. Biochemistry and Pharmacology. 2021. In press.