Synergistic combination of Proteolysis Targeting Chimera with a translational formulation for the treatment of intractable lung carcinoma

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Abstract Lung cancer is one of the most aggressive malignant tumors with non-small cell lung cancer (NSCLC) accounting for 85 % of the total cases. As per American Cancer Society, estimated new cases of lung cancer in 2020 were 228,820. Given that more than 60% of non-small cell lung carcinomas (NSCLCs) express EGFR, Tyrosine Kinase Inhibitors targeting EGFR became first- line treatments. Despite robust clinical benefits, vast majority of patients develop resistance to treatment within few months due to either T790M or C797S mutations. In regard to this, countless strides have been discovered and explored, but a remedy still remains subtle for the vast majority of lung cancer patients with EGFR mutations. Considering the central role of KRAS, MYC and EGFR in lung cancer progression, metastasis and resistance, we hypothesized that simultaneously targeting these three key oncogenic drives could be a promising approach. In our laboratory, we have identified and characterized the synergistically lethal combination of PROteolysis TArgeting Chimera (PROTAC) selectively degrading - EGFR and BRD4. Drug delivery of PROTAC class of molecules is very challenging. Drug delivery technology and route of administration play a paramount role in achieving effective concentration, minimizing off target side effects and improving patient compliance. Therefore, we propose to develop a self-injectable extended-release depot of BPRO+EPRO and evaluate anticancer efficacy in lung cancer xenograft model with different EGFR mutation status. We propose two specific aims: Specific aim 1. Optimization of BPRO and EPRO loaded depot formulation (BERD) and In vitro assays to evaluate selectivity Specific aim 2. Anticancer efficacy study of BERD in EGFR-TKIs sensitive and EGFR-TKIs resistant human lung carcinoma xenograft model. Considering the lacuna of therapeutic alternatives for the treatment of TKIs resistant lung cancer, the proposed project has significant clinical relevance.