Title of Research: PROTAC-mediated BCL-XL degradation is an effective therapeutic strategy in SCLC
Additional Authors: D. Thummuri; P. Kellish; N. Hua; P. Zhang; X. Zhang; J. Wiegand; G. Zheng; M. Zajac-Kaye; F. Kaye; D. Zhou.
Small-cell lung cancer (SCLC) is a high-grade neuroendocrine cancer with dismal prognosis, poor survival and limited therapeutic options. Antiapoptotic proteins including BCL-2, BCL-XL and MCL-1 are important therapeutic targets in SCLC. BCL-XL/BCL-2 inhibitor ABT263 showed potent antitumor activity in preclinical models, but limited efficacy in phase II trials due to dose-limiting thrombocytopenia. Therefore, in the present study we investigated the potential of our platelet-sparing BCL-XL PROTAC (DT2216) for the treatment of SCLC. We found that most SCLC cell lines are dependent on BCL-XL and are highly sensitive to DT2216, whereas BCL-XL/BCL-2-dependent cell lines were synergistically killed when DT2216 was combined with venetoclax (a selective BCL-2 inhibitor). However, some SCLC cell lines showed co-dependency on BCL-XL and MCL-1. Unfortunately, co-targeting MCL-1 and BCL-XL with their inhibitors indiscriminately kills both cancer and normal cells. To overcome this selectivity issue, we screened several inhibitors of selected tumorigenic pathways that are known to upregulate MCL-1 expression and found that the mTORC1/2 inhibitor AZD8055 selectively downregulates MCL-1 in tumor cells. More importantly, combining AZD8055 with DT2216 synergistically reduces the viability of BCL-XL/MCL-1 co-dependent SCLC cells, but not normal bronchial epithelial and other normal cells. In vivo, DT2216 potently inhibited tumor growth and extended the survival of mice accompanied with BCL-XL degradation in tumors without causing significant thrombocytopenia. Collectively, these results suggest that DT2216 could be developed as a safe and effective antitumor agent against SCLC either alone or in rational combinations.
About the author
I am working as a Postdoctoral Associate in the Department of Pharmacodynamics, College of Pharmacy. The general goal of my postdoctoral research is to selectively target Bcl-2 family of pro-survival proteins (such as Bcl-xl and Bcl-2) for proteasomal degradation in cancer cells by using proteolysis targeting chimera (PROTAC) technology, thereby reducing dose-limiting and on-target toxicities caused by Bcl–xl/Bcl-2 inhibitors while maintaining similar or improved potency. We found that Bcl-xl PROTACs can selectively induce Bcl-xl degradation in cancer cells but not in platelets leading to potent antitumor activity with reduced thrombocytopenia, because platelets depend on Bcl-xl for their survival. These findings were published in Nature Medicine (Khan S et al. Nat Med. 25: 1938-1947, 2019). In addition to providing survival advantage to cancer cells, Bcl-2 pro-survival proteins including Bcl-xl also play pivotal role in developing resistance to chemo- and targeted therapies. Therefore, another major goal of my research is to devise better therapeutic strategies aimed at targeting different tumor types by combining Bcl-xl PROTACs with standard-of-care therapies or clinical drug candidates. To achieve my research goals, I use several molecular and cell biology techniques, animal models and advanced biophysical technologies. Before joining postdoc, I completed my Ph.D. from the Central Drug Research Institute in India, where I studied the role of epithelial-mesenchymal transition (EMT) in breast cancer metastasis and therapeutic strategies to inhibit EMT and metastatic progression. While pursuing Ph.D., I was conferred with outstanding research scholar and best thesis awards to recognize my accomplishments. I have presented my research in many symposiums and scientific meetings, and have published 23 research/review articles and one book chapter.