<b>DRUGGING THE UNDRUGGABLE PROTEIN TYROSINE PHOSPHATASES FOR CANCER THERAPY: EXPECTED AND UNEXPECTED</b>
Creators: name: Miao, Yiming
Publisher: name: Purdue University Graduate School
Year: 2024
Subjects: classificationCode: 310111
subject: Signal transduction
classificationCode: 320409
subject: Tumour immunology
classificationCode: 321499
subject: Pharmacology and pharmaceutical sciences not elsewhere classified

description: Protein tyrosine phosphorylation is a key post-translational modification that drives numerous cell signaling pathways governing cell proliferation, differentiation, and transcriptional activation. Protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs) coordinate the protein tyrosine phosphorylation levels while dysregulated PTKs or PTPs activity results in aberrant protein tyrosine phosphorylation levels and cause multiple human diseases including cancer, diabetes, and autoimmune diseases. Targeting PTKs using small molecule inhibitors or antibodies achieved many successes for various indications. For example, targeting epidermal growth factor receptor for cancer therapy and targeting Janus kinase 2 for autoimmune diseases. Meanwhile, targeting PTPs as therapeutic approaches remains underexplored due to the limited understanding of PTP biology and challenging inhibitor development.<br>So far, many substrates and pathological mechanisms of PTPs remain elusive. As an example, although it is well recognized that Phosphatases of Regenerating Liver (PRL) family members PRL1/2/3 are overexpressed in the majority of cancer types and are frequently associated with poor clinical outcomes, the pathological mechanism of PRLs is unclear due to the limited understanding of their substrates. In the presented study, I focused on understanding the oncogenic mechanisms of PRL2 phosphatase and the therapeutic potential of targeting PRL2. I developed the first breast-specific PRL2 deletion mouse model to understand the role of PRL2 in estrogen receptor-positive breast tumorigenesis driven by the aberrant PI3K/AKT signaling, which represents over 30% of the human breast cancer population. I found PRL2 deletion drastically extended the median tumor-free survival of mice harboring PI3K gain-of-function mutant from 377 days to 605 days while such extension was invalidated in the absence of PTEN, a major tumor suppressor and one of the substrates of PRL2.<br>PTPs are challenging targets for inhibitor development due to the highly conserved and positively charged active site. Most of the identified PTP inhibitors lack the selectivity as a chemical probe for interrogating the PTP biology and are negatively charged which limits their bioavailability as a therapeutic approach. To overcome these defects, we utilized the proteolysis targeting chimera (PROTACs) technique to generate bifunctional small molecules that recruit the protein of interest to an E3 ligase for protein ubiquitination and proteasome degradation. Compared with the traditional occupancy-based inhibitors, PROTACs have improved efficacy and selectivity due to the catalytic degradation turnover and the necessity of the formation of the target-PROTAC-E3 complex. We developed the first-in-class PTP1B/TC-PTP dual degrader named DU-14 and TC-PTP selective degrader named TP1L for cancer immunotherapy. Protein tyrosine phosphatase 1B (PTP1B) and T-cell protein tyrosine phosphatase (TC-PTP) play non-redundant negative regulatory roles in T-cell activation and tumor antigen presentation. Previous studies have shown that the deletion of these two PTPs elicits potent anti-tumor immunity in vivo. I have shown that DU-14 and TP1L efficiently degrade their corresponding target with outstanding selectivity and elevate the cytokine-mediated phosphorylation of their substrates. As a result, I have shown that DU-14 and TP1L elicit potent anti-tumor immunity using co-culture or in vivo tumor models.<br>I also discovered an unexpected but beneficial off-target effect of SHP2 allosteric inhibitors under clinical trial and investigated its therapeutic implications for aberrant RAS-driven cancers. Aberrant activation of RAS-MAPK signaling is common in cancer, and efforts to inhibit pathway components have yielded drugs with promising clinical activities. As a central node essential for receptor tyrosine kinase-mediated RAS activation, SHP2 has emerged as an attractive cancer target. Consequently, many SHP2 allosteric inhibitors are now in clinical testing. I discovered a previously unrecognized off-target effect associated with SHP2 allosteric inhibitors. I showed that off-target autophagy inhibition by SHP2 allosteric inhibitors contributes to their anti-tumor activity. Finally, I exemplified a new therapeutic framework that harnesses both the on- and off-target activities of SHP2 allosteric inhibitors for improved treatment of mutant RAS-driven and drug-resistant malignancies such as pancreatic and colorectal cancers.<br>In summary, these studies facilitate the understanding of PTP disease biology and provide examples of successful strategies in developing small molecule PTP inhibitors for cancer therapy.