Author ORCID Identifier
https://orcid.org/0009-0001-0189-3619
Date Available
10-31-2025
Year of Publication
2024
Document Type
Doctoral Dissertation
Degree Name
Doctor of Philosophy (PhD)
College
Medicine
Department/School/Program
Toxicology and Cancer Biology
Advisor
Vivek Rangnekar
Abstract
Most tumors initially respond to treatment, yet refractory clones subsequently develop owing to resistance mechanisms which can be classified as intrinsic or extrinsic resistance. The intrinsic resistance is usually present prior to any treatment whereas the extrinsic resistance develops as a result of exposure to some kind of therapy. In order to target these “therapy resistant” tumor cells an unbiased screen of an FDA-approved drug library against cancer cells was performed. This was followed by synthesis of chemical analogs of the most effective drug.
The studies led to the identification of a derivative of the antihistamine drug ebastine, designated Super-ebastine (Super-EBS), that inhibited cell viability and xenograft growth of tumors representing models of plasticity and treatment resistance. Interestingly, computation modeling, pull-down with biotinylated compounds, and validation experiments indicated that Super-EBS inhibited over 800 diverse cancer cell lines tested and targeted the serine/threonine kinase RPS6KB1 (p70S6K or S6K1), but not mTORC1, its upstream activator. RPS6KB1 is upregulated in diverse cancers such as lung, prostate, breast, esophagus carcinoma relative to counterpart normal/benign tissues and phosphorylated-RPS6KB1 predicts poor prognosis for cancer patients. Inhibition of RPS6KB1 phosphorylation was necessary for tumor cell growth inhibition, and restoration of phospho-RPS6KB1 above endogenous levels rendered tumor cells resistant to Super-EBS. Inhibition of RPS6KB1 phosphorylation by Super-EBS induced caspase 2 dependent apoptosis via inhibition of the Cdc42/Rac-1/p-PAK1 pathway that led to actin depolymerization and caspase 2 activation. The essential role of RPS6KB1 was recapitulated in mouse models, and knockout of RPS6KB1 abrogated tumor growth in mice. Thus, phospho-RPS6KB1 is a critical target for overcoming intrinsic and acquired cancer resistance to therapy.
Digital Object Identifier (DOI)
https://doi.org/10.13023/etd.2024.370
Recommended Citation
Ganguly, Saptadwipa, "RPS6KB1 IS A CRITICAL TARGET FOR OVERCOMING TUMOR LINEAGE PLASTICITY AND THERAPY RESISTANCE" (2024). Theses and Dissertations--Toxicology and Cancer Biology. 59.
https://uknowledge.uky.edu/toxicology_etds/59
