Co-targeting BCL-XL and MCL-1 with DT2216 and AZD8055 synergistically inhibits small-cell lung cancer growth without causing on-target toxicities in mice

KHAN, S.; Kellish, P.; Connis, N.; Thummuri, D.; Wiegand, J.; Zhang, P.; Zhang, X.; Budamagunta, V.; Hua, N.; Yang, Y.; De, U.; Jin, L.; Zhang, W.; Zheng, G.; Hromas, R.; Hann, C.; Zajac-Kaye, M.; Kaye, F. J.; Zhou, D.

doi:10.1101/2022.09.12.507616

bioRxiv · 10.1101/2022.09.12.507616

Co-targeting BCL-XL and MCL-1 with DT2216 and AZD8055 synergistically inhibits small-cell lung cancer growth without causing on-target toxicities in mice

KHAN, S.·Kellish, P.·Connis, N.·Thummuri, D.·Wiegand, J.·Zhang, P.·Zhang, X.·Budamagunta, V.·Hua, N.·Yang, Y.·De, U.·Jin, L.·Zhang, W.·Zheng, G.·Hromas, R.·Hann, C.·Zajac-Kaye, M.·Kaye, F. J.·Zhou, D.

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Abstract

Small-cell lung cancer (SCLC) is an aggressive malignancy with limited therapeutic options. The dismal prognosis in SCLC is in part associated with an upregulation of BCL-2 family anti-apoptotic proteins, including BCL-XL and MCL-1. Unfortunately, the currently available inhibitors of BCL-2 family anti-apoptotic proteins, except BCL-2 inhibitors, are not clinically relevant because of various on-target toxicities. We, therefore, aimed to develop an effective and safe strategy targeting these anti-apoptotic proteins with DT2216 (our platelet-sparing BCL-XL degrader) and AZD8055 (an mTOR inhibitor) to avoid associated on-target toxicities while synergistically optimizing tumor response. Through BH3 mimetic screening, we identified a subset of SCLC cell lines that is co-dependent on BCL-XL and MCL-1. After screening inhibitors of selected tumorigenic pathways, we found that AZD8055 selectively downregulates MCL-1 in SCLC cells and its combination with DT2216 synergistically killed BCL-XL/MCL-1 co-dependent SCLC cells, but not normal cells. Mechanistically, the combination caused BCL-XL degradation and suppression of MCL1 expression, and thus disrupted MCL-1 interaction with BIM leading to an enhanced apoptotic induction. In vivo, DT2216+AZD8055 combination significantly inhibited the growth of cell line-derived and patient-derived xenografts and reduced tumor burden accompanied with extended survival in a genetically-engineered mouse (GEM) model of SCLC without causing significant thrombocytopenia or other normal tissue injury. Thus, these preclinical findings lay a strong foundation for future clinical studies to test DT2216+mTOR inhibitor combination in a subset of SCLC patients whose tumors are co-driven by BCL-XL and MCL-1.

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KHAN, S., Kellish, P., Connis, N., Thummuri, D., Wiegand, J., Zhang, P., Zhang, X., Budamagunta, V., Hua, N., Yang, Y., De, U., Jin, L., Zhang, W., Zheng, G., Hromas, R., Hann, C., Zajac-Kaye, M., Kaye, F. J., Zhou, D.. 2022-09-14. Co-targeting BCL-XL and MCL-1 with DT2216 and AZD8055 synergistically inhibits small-cell lung cancer growth without causing on-target toxicities in mice. https://doi.org/10.1101/2022.09.12.507616

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