Modulation of Bax and mTOR for cancer therapeutics

Rui Li; Chunyong Ding; Jun Zhang; Maohua Xie; Dongkyoo Park; Ye Ding; Guo Chen; Guojing Zhang; Melissa Gilbert-Ross; Wei Zhou; Adam I. Marcus; Shi Yong Sun; Zhuo G. Chen; Gabriel L. Sica; Suresh S. Ramalingam; Andrew T. Magis; Haian Fu; Fadlo R. Khuri; Walter J. Curran; Taofeek K. Owonikoko; Dong M. Shin; Jia Zhou; Xingming Deng

doi:10.1158/0008-5472.CAN-16-2356

Modulation of Bax and mTOR for cancer therapeutics

Rui Li, Chunyong Ding, Jun Zhang, Maohua Xie, Dongkyoo Park, Ye Ding, Guo Chen, Guojing Zhang, Melissa Gilbert-Ross, Wei Zhou, Adam I. Marcus, Shi Yong Sun, Zhuo G. Chen, Gabriel L. Sica, Suresh S. Ramalingam, Andrew T. Magis, Haian Fu, Fadlo R. Khuri, Walter J. Curran, Taofeek K. OwonikokoDong M. Shin, Jia Zhou, Xingming Deng

Pharmacology & Toxicology

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

Abstract

A rationale exists for pharmacologic manipulation of the serine (S)184 phosphorylation site of the proapoptotic Bcl2 family member Bax as an anticancer strategy. Here, we report the refinement of the Bax agonist SMBA1 to generate CYD-2-11, which has characteristics of a suitable clinical lead compound. CYD-2-11 targeted the structural pocket proximal to S184 in the C-terminal region of Bax, directly activating its proapoptotic activity by inducing a conformational change enabling formation of Bax homooligomers in mitochondrial membranes. In murine models of small-cell and non-small cell lung cancers, including patient-derived xenograft and the genetically engineered mutant KRAS-driven lung cancer models, CYD-2-11 suppressed malignant growth without evident significant toxicity to normal tissues. In lung cancer patients treated with mTOR inhibitor RAD001, we observed enhanced S184 Bax phosphorylation in lung cancer cells and tissues that inactivates the propaoptotic function of Bax, contributing to rapalog resistance. Combined treatment of CYD-2-11 and RAD001 in murine lung cancer models displayed strong synergistic activity and overcame rapalog resistance in vitro and in vivo. Taken together, our findings provide preclinical evidence for a pharmacologic combination of Bax activation and mTOR inhibition as a rational strategy to improve lung cancer treatment.

Original language	English (US)
Pages (from-to)	3001-3012
Number of pages	12
Journal	Cancer Research
Volume	77
Issue number	11
DOIs	https://doi.org/10.1158/0008-5472.CAN-16-2356
State	Published - Jun 1 2017

ASJC Scopus subject areas

Oncology
Cancer Research

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Li, R., Ding, C., Zhang, J., Xie, M., Park, D., Ding, Y., Chen, G., Zhang, G., Gilbert-Ross, M., Zhou, W., Marcus, A. I., Sun, S. Y., Chen, Z. G., Sica, G. L., Ramalingam, S. S., Magis, A. T., Fu, H., Khuri, F. R., Curran, W. J., ... Deng, X. (2017). Modulation of Bax and mTOR for cancer therapeutics. Cancer Research, 77(11), 3001-3012. https://doi.org/10.1158/0008-5472.CAN-16-2356

Li, R, Ding, C, Zhang, J, Xie, M, Park, D, Ding, Y, Chen, G, Zhang, G, Gilbert-Ross, M, Zhou, W, Marcus, AI, Sun, SY, Chen, ZG, Sica, GL, Ramalingam, SS, Magis, AT, Fu, H, Khuri, FR, Curran, WJ, Owonikoko, TK, Shin, DM, Zhou, J & Deng, X 2017, 'Modulation of Bax and mTOR for cancer therapeutics', Cancer Research, vol. 77, no. 11, pp. 3001-3012. https://doi.org/10.1158/0008-5472.CAN-16-2356

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title = "Modulation of Bax and mTOR for cancer therapeutics",

abstract = "A rationale exists for pharmacologic manipulation of the serine (S)184 phosphorylation site of the proapoptotic Bcl2 family member Bax as an anticancer strategy. Here, we report the refinement of the Bax agonist SMBA1 to generate CYD-2-11, which has characteristics of a suitable clinical lead compound. CYD-2-11 targeted the structural pocket proximal to S184 in the C-terminal region of Bax, directly activating its proapoptotic activity by inducing a conformational change enabling formation of Bax homooligomers in mitochondrial membranes. In murine models of small-cell and non-small cell lung cancers, including patient-derived xenograft and the genetically engineered mutant KRAS-driven lung cancer models, CYD-2-11 suppressed malignant growth without evident significant toxicity to normal tissues. In lung cancer patients treated with mTOR inhibitor RAD001, we observed enhanced S184 Bax phosphorylation in lung cancer cells and tissues that inactivates the propaoptotic function of Bax, contributing to rapalog resistance. Combined treatment of CYD-2-11 and RAD001 in murine lung cancer models displayed strong synergistic activity and overcame rapalog resistance in vitro and in vivo. Taken together, our findings provide preclinical evidence for a pharmacologic combination of Bax activation and mTOR inhibition as a rational strategy to improve lung cancer treatment.",

author = "Rui Li and Chunyong Ding and Jun Zhang and Maohua Xie and Dongkyoo Park and Ye Ding and Guo Chen and Guojing Zhang and Melissa Gilbert-Ross and Wei Zhou and Marcus, {Adam I.} and Sun, {Shi Yong} and Chen, {Zhuo G.} and Sica, {Gabriel L.} and Ramalingam, {Suresh S.} and Magis, {Andrew T.} and Haian Fu and Khuri, {Fadlo R.} and Curran, {Walter J.} and Owonikoko, {Taofeek K.} and Shin, {Dong M.} and Jia Zhou and Xingming Deng",

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doi = "10.1158/0008-5472.CAN-16-2356",

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AU - Li, Rui

AU - Ding, Chunyong

AU - Zhang, Jun

AU - Xie, Maohua

AU - Park, Dongkyoo

AU - Ding, Ye

AU - Chen, Guo

AU - Zhang, Guojing

AU - Gilbert-Ross, Melissa

AU - Zhou, Wei

AU - Marcus, Adam I.

AU - Sun, Shi Yong

AU - Chen, Zhuo G.

AU - Sica, Gabriel L.

AU - Ramalingam, Suresh S.

AU - Magis, Andrew T.

AU - Fu, Haian

AU - Khuri, Fadlo R.

AU - Curran, Walter J.

AU - Owonikoko, Taofeek K.

AU - Shin, Dong M.

AU - Zhou, Jia

AU - Deng, Xingming

PY - 2017/6/1

Y1 - 2017/6/1

N2 - A rationale exists for pharmacologic manipulation of the serine (S)184 phosphorylation site of the proapoptotic Bcl2 family member Bax as an anticancer strategy. Here, we report the refinement of the Bax agonist SMBA1 to generate CYD-2-11, which has characteristics of a suitable clinical lead compound. CYD-2-11 targeted the structural pocket proximal to S184 in the C-terminal region of Bax, directly activating its proapoptotic activity by inducing a conformational change enabling formation of Bax homooligomers in mitochondrial membranes. In murine models of small-cell and non-small cell lung cancers, including patient-derived xenograft and the genetically engineered mutant KRAS-driven lung cancer models, CYD-2-11 suppressed malignant growth without evident significant toxicity to normal tissues. In lung cancer patients treated with mTOR inhibitor RAD001, we observed enhanced S184 Bax phosphorylation in lung cancer cells and tissues that inactivates the propaoptotic function of Bax, contributing to rapalog resistance. Combined treatment of CYD-2-11 and RAD001 in murine lung cancer models displayed strong synergistic activity and overcame rapalog resistance in vitro and in vivo. Taken together, our findings provide preclinical evidence for a pharmacologic combination of Bax activation and mTOR inhibition as a rational strategy to improve lung cancer treatment.

AB - A rationale exists for pharmacologic manipulation of the serine (S)184 phosphorylation site of the proapoptotic Bcl2 family member Bax as an anticancer strategy. Here, we report the refinement of the Bax agonist SMBA1 to generate CYD-2-11, which has characteristics of a suitable clinical lead compound. CYD-2-11 targeted the structural pocket proximal to S184 in the C-terminal region of Bax, directly activating its proapoptotic activity by inducing a conformational change enabling formation of Bax homooligomers in mitochondrial membranes. In murine models of small-cell and non-small cell lung cancers, including patient-derived xenograft and the genetically engineered mutant KRAS-driven lung cancer models, CYD-2-11 suppressed malignant growth without evident significant toxicity to normal tissues. In lung cancer patients treated with mTOR inhibitor RAD001, we observed enhanced S184 Bax phosphorylation in lung cancer cells and tissues that inactivates the propaoptotic function of Bax, contributing to rapalog resistance. Combined treatment of CYD-2-11 and RAD001 in murine lung cancer models displayed strong synergistic activity and overcame rapalog resistance in vitro and in vivo. Taken together, our findings provide preclinical evidence for a pharmacologic combination of Bax activation and mTOR inhibition as a rational strategy to improve lung cancer treatment.

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ER -

Modulation of Bax and mTOR for cancer therapeutics

Abstract

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