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

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)3001-3012
Number of pages12
JournalCancer Research
Volume77
Issue number11
DOIs
StatePublished - Jun 1 2017

Fingerprint

Lung Neoplasms
Neoplasms
Phosphorylation
Therapeutics
Mitochondrial Membranes
Heterografts
Non-Small Cell Lung Carcinoma
Serine
Growth
Everolimus

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Li, R., Ding, C., Zhang, J., Xie, M., Park, D., Ding, Y., ... 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

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

In: Cancer Research, Vol. 77, No. 11, 01.06.2017, p. 3001-3012.

Research output: Contribution to journalArticle

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
Li R, Ding C, Zhang J, Xie M, Park D, Ding Y et al. Modulation of Bax and mTOR for cancer therapeutics. Cancer Research. 2017 Jun 1;77(11):3001-3012. https://doi.org/10.1158/0008-5472.CAN-16-2356
Li, Rui ; Ding, Chunyong ; Zhang, Jun ; Xie, Maohua ; Park, Dongkyoo ; Ding, Ye ; Chen, Guo ; Zhang, Guojing ; Gilbert-Ross, Melissa ; Zhou, Wei ; Marcus, Adam I. ; Sun, Shi Yong ; Chen, Zhuo G. ; Sica, Gabriel L. ; Ramalingam, Suresh S. ; Magis, Andrew T. ; Fu, Haian ; Khuri, Fadlo R. ; Curran, Walter J. ; Owonikoko, Taofeek K. ; Shin, Dong M. ; Zhou, Jia ; Deng, Xingming. / Modulation of Bax and mTOR for cancer therapeutics. In: Cancer Research. 2017 ; Vol. 77, No. 11. pp. 3001-3012.
@article{913e8027210e45639656c8b2b75f4b75,
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",
year = "2017",
month = "6",
day = "1",
doi = "10.1158/0008-5472.CAN-16-2356",
language = "English (US)",
volume = "77",
pages = "3001--3012",
journal = "Journal of Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "11",

}

TY - JOUR

T1 - Modulation of Bax and mTOR for cancer therapeutics

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.

UR - http://www.scopus.com/inward/record.url?scp=85020799913&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85020799913&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-16-2356

DO - 10.1158/0008-5472.CAN-16-2356

M3 - Article

C2 - 28381544

AN - SCOPUS:85020799913

VL - 77

SP - 3001

EP - 3012

JO - Journal of Cancer Research

JF - Journal of Cancer Research

SN - 0008-5472

IS - 11

ER -