ADVANCING CANCER TREATMENT USING PROTAC CHEMICALS AND VITAMIN C

Cancer is one of the leading death-causing disease worldwide and most of them are still hard to be eradicated by current cancer therapies. Hence, there is an urgent need of developing novel cancer treatments. Here, we designed and synthesized epidermal growth factor receptor (EGFR) degraders using proteolysis-targeting chimera (PROTAC) technology to induce EGFR ubiquitination and degradation, for the treatment of non-small-cell lung cancer (NSCLC). Our EGFR degraders efficiently, reversibly and selectively induce the degradation of mutant EGFR, which is the driver of EGFR-mutant NSCLC. These EGFR degraders are able to inhibit EGFR-mutant NSCLC cell growth with sufficient pharmacokinetic properties. This work shows the feasibility of treating NSCLC with potential EGFR PROTACs (Chapter 2). Interestingly, we found when pre-treated with a phosphoinositide 3-kinases (PI3K) inhibitor, pictilisib, our degraders were able to induce the WT EGFR degradation through promoting ternary complex formation. Mechanistically, I have confirmed that both proteasome and lysosome mediated protein degradation pathways are involved in EGFR PROTACs. This study showed for the first time that downstream signal inhibition could promote PROTAC induced WT EGFR degradation. Meanwhile, this work raised a possible route to achieve WT EGFR degradation as potential PROTAC drugs for NSCLC patients driven by the overexpression of WT EGFR (Chapter 3). In addition to our PROTAC studies, we also found high-dose Vitamin C (VC) could significantly enhance tumor immunotherapy efficacy when combined with immune checkpoint inhibitors. Single-cell RNA-Seq indicated a novel role of VC in promoting tumor MHC class I antigen presentation and this function relies on the expression of the tumor TET2 gene. We found VC directly binds to TET2 and increases its enzymatic activity to induce antigen presenting gene expression in tumor cells. This study provides a potential way of enhancing clinical checkpoint inhibitor efficacy by the combined treatment with high-dose VC (Chapter 4). Together, these chapters extend our tool base of novel cancer therapeutics, providing new insights on the emerging PROTAC technology and the promising immune checkpoint inhibitor combined therapy for clinical cancer treatment.