Date of Award
Open Access Dissertation
College of Pharmacy
Breast cancers (BrCa) that overexpress oncogenic tyrosine kinase receptor HER2 are treated with HER2-targeting antibodies (such as trastuzumab) or small-molecule kinase inhibitors (such as lapatinib). However, most patients with metastatic HER2+ BrCa have intrinsic resistance and nearly all eventually become resistant to HER2-targeting therapy. Resistance to HER2-targeting drugs frequently involves transcriptional reprogramming associated with constitutive activation of different signaling pathways. We have investigated the role of CDK8/19 Mediator kinase, a regulator of transcriptional reprogramming, in the response of HER2+ BrCa to HER2-targeting drugs. Selective CDK8/19 inhibitors (senexin B and SNX631) showed synergistic interactions with lapatinib and trastuzumab in a panel of HER2+ BrCa cell lines, overcoming and preventing resistance to HER2-targeting drugs. The synergistic effects were mediated in part through the PI3K/AKT/mTOR pathway and reduced by PI3K inhibition. Combination of HER2- and CDK8/19-targeting agents inhibited STAT1 and STAT3 phosphorylation at S727 and upregulated tumor suppressor BTG2. The growth of xenograft tumors formed by lapatinib-sensitive or resistant HER2+ breast cancer cells was partially inhibited by SNX631 alone and strongly suppressed by the combination of SNX631 and lapatinib, overcoming lapatinib resistance. These effects were associated with decreased tumor cell proliferation and altered recruitment of stromal components to the xenograft tumors.
Triple negative breast cancer (TNBC) is the most aggressive subtype of all breast cancers, however, unlike other subtypes, which have relatively more treatment options, current treatments for TNBC are restricted and this scarcity of viable options is the key contributor to poorer prognosis. Despite early response, almost all the targeted drugs tested in TNBC eventually fail due to the development of resistance. Here we analyzed the effect of CDK8/19 inhibition on the outcome of treatment with mTORC1 inhibitor everolimus (RAD001), an approved drug for several cancers with mutations of PTEN or PI3KCA. In vivo treatment with everolimus in a TNBC xenograft model achieved remarkable tumor growth inhibition but all the tumors eventually developed resistance. However, the addition of a CDK8/19 inhibitor prevented the emergence of everolimus resistance in all the tumors. RNA-Seq analysis demonstrated that this effect was due to the prevention of transcriptional reprogramming associated with everolimus resistance in tumor cells.
In summary, targeting CDK8/19 has exhibited potential clinical benefits, either as a single agent or in combination with lapatinib or everolimus, for HER2- positive and triple-negative breast cancers.
Ding, X.(2022). Mediator Kinase Inhibitors for Breast Cancer Therapy. (Doctoral dissertation). Retrieved from https://scholarcommons.sc.edu/etd/6588
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