Dual mTOR Kinase Inhibitor MLN0128 Sensitizes HR+/HER2+ Breast Cancer Patient-Derived Xenografts to Trastuzumab or Fulvestrant

Publication Date:
2018-01-17
Publisher:
The American Association for Cancer Research (AACR)
Print ISSN:
1078-0432
Electronic ISSN:
1557-3265
Topics:
Medicine
Published by:
http://www.aacr.org/
_version_ 1836398751806128128
autor Hsu, P.-Y., Wu, V. S., Kanaya, N., Petrossian, K., Hsu, H.-K., Nguyen, D., Schmolze, D., Kai, M., Liu, C.-Y., Lu, H., Chu, P., Vito, C. A., Kruper, L., Mortimer, J., Chen, S.
beschreibung Purpose: Therapeutic strategies against hormonal receptor–positive (HR + )/HER2 + breast cancers with poor response to trastuzumab need to be optimized. Experimental Design: Two HR + /HER2 + patient-derived xenograft (PDX) models named as COH-SC1 and COH-SC31 were established to explore targeted therapies for HER2 + breast cancers. RNA sequencing and RPPA (reverse phase protein array) analyses were conducted to decipher molecular features of the two PDXs and define the therapeutic strategy of interest, validated by in vivo drug efficacy examination and in vitro cell proliferation analysis. Results: Estrogen acted as a growth driver of trastuzumab-resistant COH-SC31 tumors but an accelerator in the trastuzumab-sensitive COH-SC1 model. In vivo trastuzumab efficacy examination further confirmed the consistent responses between PDXs and the corresponding tumors. Integrative omics analysis revealed that mammalian target of rapamycin (mTOR) and ERα signaling predominantly regulate tumor growth of the two HR + /HER2 + PDXs. Combination of the dual mTOR complex inhibitor MLN0128 and anti-HER2 trastuzumab strongly suppressed tumor growth of COH-SC1 PDX accompanied by increasing ER-positive cell population in vivo . Instead, MLN0128 in combination with antiestrogen fulvestrant significantly halted the growth of HR + /HER2 + cancer cells in vitro and trastuzumab-resistant COH-SC31 as well as trastuzumab-sensitive COH-SC1 tumors in vivo . Conclusions: Compared with the standard trastuzumab treatment, this study demonstrates alternative therapeutic strategies against HR + /HER2 + tumors through establishment of two PDXs coupled with integrative omics analyses and in vivo drug efficacy examination. This work presents a prototype of future "co-clinical" trials to tailor personalized medicine in clinical practice. Clin Cancer Res; 24(2); 395–406. ©2017 AACR .
citation_standardnr 6139904
datenlieferant ipn_articles
feed_id 9363
feed_publisher The American Association for Cancer Research (AACR)
feed_publisher_url http://www.aacr.org/
insertion_date 2018-01-17
journaleissn 1557-3265
journalissn 1078-0432
publikationsjahr_anzeige 2018
publikationsjahr_facette 2018
publikationsjahr_intervall 7984:2015-2019
publikationsjahr_sort 2018
publisher The American Association for Cancer Research (AACR)
quelle Clinical Cancer Research
relation http://clincancerres.aacrjournals.org/cgi/content/short/24/2/395?rss=1
search_space articles
shingle_author_1 Hsu, P.-Y., Wu, V. S., Kanaya, N., Petrossian, K., Hsu, H.-K., Nguyen, D., Schmolze, D., Kai, M., Liu, C.-Y., Lu, H., Chu, P., Vito, C. A., Kruper, L., Mortimer, J., Chen, S.
shingle_author_2 Hsu, P.-Y., Wu, V. S., Kanaya, N., Petrossian, K., Hsu, H.-K., Nguyen, D., Schmolze, D., Kai, M., Liu, C.-Y., Lu, H., Chu, P., Vito, C. A., Kruper, L., Mortimer, J., Chen, S.
shingle_author_3 Hsu, P.-Y., Wu, V. S., Kanaya, N., Petrossian, K., Hsu, H.-K., Nguyen, D., Schmolze, D., Kai, M., Liu, C.-Y., Lu, H., Chu, P., Vito, C. A., Kruper, L., Mortimer, J., Chen, S.
shingle_author_4 Hsu, P.-Y., Wu, V. S., Kanaya, N., Petrossian, K., Hsu, H.-K., Nguyen, D., Schmolze, D., Kai, M., Liu, C.-Y., Lu, H., Chu, P., Vito, C. A., Kruper, L., Mortimer, J., Chen, S.
shingle_catch_all_1 Dual mTOR Kinase Inhibitor MLN0128 Sensitizes HR+/HER2+ Breast Cancer Patient-Derived Xenografts to Trastuzumab or Fulvestrant
Purpose: Therapeutic strategies against hormonal receptor–positive (HR + )/HER2 + breast cancers with poor response to trastuzumab need to be optimized. Experimental Design: Two HR + /HER2 + patient-derived xenograft (PDX) models named as COH-SC1 and COH-SC31 were established to explore targeted therapies for HER2 + breast cancers. RNA sequencing and RPPA (reverse phase protein array) analyses were conducted to decipher molecular features of the two PDXs and define the therapeutic strategy of interest, validated by in vivo drug efficacy examination and in vitro cell proliferation analysis. Results: Estrogen acted as a growth driver of trastuzumab-resistant COH-SC31 tumors but an accelerator in the trastuzumab-sensitive COH-SC1 model. In vivo trastuzumab efficacy examination further confirmed the consistent responses between PDXs and the corresponding tumors. Integrative omics analysis revealed that mammalian target of rapamycin (mTOR) and ERα signaling predominantly regulate tumor growth of the two HR + /HER2 + PDXs. Combination of the dual mTOR complex inhibitor MLN0128 and anti-HER2 trastuzumab strongly suppressed tumor growth of COH-SC1 PDX accompanied by increasing ER-positive cell population in vivo . Instead, MLN0128 in combination with antiestrogen fulvestrant significantly halted the growth of HR + /HER2 + cancer cells in vitro and trastuzumab-resistant COH-SC31 as well as trastuzumab-sensitive COH-SC1 tumors in vivo . Conclusions: Compared with the standard trastuzumab treatment, this study demonstrates alternative therapeutic strategies against HR + /HER2 + tumors through establishment of two PDXs coupled with integrative omics analyses and in vivo drug efficacy examination. This work presents a prototype of future "co-clinical" trials to tailor personalized medicine in clinical practice. Clin Cancer Res; 24(2); 395–406. ©2017 AACR .
Hsu, P.-Y., Wu, V. S., Kanaya, N., Petrossian, K., Hsu, H.-K., Nguyen, D., Schmolze, D., Kai, M., Liu, C.-Y., Lu, H., Chu, P., Vito, C. A., Kruper, L., Mortimer, J., Chen, S.
The American Association for Cancer Research (AACR)
1078-0432
10780432
1557-3265
15573265
shingle_catch_all_2 Dual mTOR Kinase Inhibitor MLN0128 Sensitizes HR+/HER2+ Breast Cancer Patient-Derived Xenografts to Trastuzumab or Fulvestrant
Purpose: Therapeutic strategies against hormonal receptor–positive (HR + )/HER2 + breast cancers with poor response to trastuzumab need to be optimized. Experimental Design: Two HR + /HER2 + patient-derived xenograft (PDX) models named as COH-SC1 and COH-SC31 were established to explore targeted therapies for HER2 + breast cancers. RNA sequencing and RPPA (reverse phase protein array) analyses were conducted to decipher molecular features of the two PDXs and define the therapeutic strategy of interest, validated by in vivo drug efficacy examination and in vitro cell proliferation analysis. Results: Estrogen acted as a growth driver of trastuzumab-resistant COH-SC31 tumors but an accelerator in the trastuzumab-sensitive COH-SC1 model. In vivo trastuzumab efficacy examination further confirmed the consistent responses between PDXs and the corresponding tumors. Integrative omics analysis revealed that mammalian target of rapamycin (mTOR) and ERα signaling predominantly regulate tumor growth of the two HR + /HER2 + PDXs. Combination of the dual mTOR complex inhibitor MLN0128 and anti-HER2 trastuzumab strongly suppressed tumor growth of COH-SC1 PDX accompanied by increasing ER-positive cell population in vivo . Instead, MLN0128 in combination with antiestrogen fulvestrant significantly halted the growth of HR + /HER2 + cancer cells in vitro and trastuzumab-resistant COH-SC31 as well as trastuzumab-sensitive COH-SC1 tumors in vivo . Conclusions: Compared with the standard trastuzumab treatment, this study demonstrates alternative therapeutic strategies against HR + /HER2 + tumors through establishment of two PDXs coupled with integrative omics analyses and in vivo drug efficacy examination. This work presents a prototype of future "co-clinical" trials to tailor personalized medicine in clinical practice. Clin Cancer Res; 24(2); 395–406. ©2017 AACR .
Hsu, P.-Y., Wu, V. S., Kanaya, N., Petrossian, K., Hsu, H.-K., Nguyen, D., Schmolze, D., Kai, M., Liu, C.-Y., Lu, H., Chu, P., Vito, C. A., Kruper, L., Mortimer, J., Chen, S.
The American Association for Cancer Research (AACR)
1078-0432
10780432
1557-3265
15573265
shingle_catch_all_3 Dual mTOR Kinase Inhibitor MLN0128 Sensitizes HR+/HER2+ Breast Cancer Patient-Derived Xenografts to Trastuzumab or Fulvestrant
Purpose: Therapeutic strategies against hormonal receptor–positive (HR + )/HER2 + breast cancers with poor response to trastuzumab need to be optimized. Experimental Design: Two HR + /HER2 + patient-derived xenograft (PDX) models named as COH-SC1 and COH-SC31 were established to explore targeted therapies for HER2 + breast cancers. RNA sequencing and RPPA (reverse phase protein array) analyses were conducted to decipher molecular features of the two PDXs and define the therapeutic strategy of interest, validated by in vivo drug efficacy examination and in vitro cell proliferation analysis. Results: Estrogen acted as a growth driver of trastuzumab-resistant COH-SC31 tumors but an accelerator in the trastuzumab-sensitive COH-SC1 model. In vivo trastuzumab efficacy examination further confirmed the consistent responses between PDXs and the corresponding tumors. Integrative omics analysis revealed that mammalian target of rapamycin (mTOR) and ERα signaling predominantly regulate tumor growth of the two HR + /HER2 + PDXs. Combination of the dual mTOR complex inhibitor MLN0128 and anti-HER2 trastuzumab strongly suppressed tumor growth of COH-SC1 PDX accompanied by increasing ER-positive cell population in vivo . Instead, MLN0128 in combination with antiestrogen fulvestrant significantly halted the growth of HR + /HER2 + cancer cells in vitro and trastuzumab-resistant COH-SC31 as well as trastuzumab-sensitive COH-SC1 tumors in vivo . Conclusions: Compared with the standard trastuzumab treatment, this study demonstrates alternative therapeutic strategies against HR + /HER2 + tumors through establishment of two PDXs coupled with integrative omics analyses and in vivo drug efficacy examination. This work presents a prototype of future "co-clinical" trials to tailor personalized medicine in clinical practice. Clin Cancer Res; 24(2); 395–406. ©2017 AACR .
Hsu, P.-Y., Wu, V. S., Kanaya, N., Petrossian, K., Hsu, H.-K., Nguyen, D., Schmolze, D., Kai, M., Liu, C.-Y., Lu, H., Chu, P., Vito, C. A., Kruper, L., Mortimer, J., Chen, S.
The American Association for Cancer Research (AACR)
1078-0432
10780432
1557-3265
15573265
shingle_catch_all_4 Dual mTOR Kinase Inhibitor MLN0128 Sensitizes HR+/HER2+ Breast Cancer Patient-Derived Xenografts to Trastuzumab or Fulvestrant
Purpose: Therapeutic strategies against hormonal receptor–positive (HR + )/HER2 + breast cancers with poor response to trastuzumab need to be optimized. Experimental Design: Two HR + /HER2 + patient-derived xenograft (PDX) models named as COH-SC1 and COH-SC31 were established to explore targeted therapies for HER2 + breast cancers. RNA sequencing and RPPA (reverse phase protein array) analyses were conducted to decipher molecular features of the two PDXs and define the therapeutic strategy of interest, validated by in vivo drug efficacy examination and in vitro cell proliferation analysis. Results: Estrogen acted as a growth driver of trastuzumab-resistant COH-SC31 tumors but an accelerator in the trastuzumab-sensitive COH-SC1 model. In vivo trastuzumab efficacy examination further confirmed the consistent responses between PDXs and the corresponding tumors. Integrative omics analysis revealed that mammalian target of rapamycin (mTOR) and ERα signaling predominantly regulate tumor growth of the two HR + /HER2 + PDXs. Combination of the dual mTOR complex inhibitor MLN0128 and anti-HER2 trastuzumab strongly suppressed tumor growth of COH-SC1 PDX accompanied by increasing ER-positive cell population in vivo . Instead, MLN0128 in combination with antiestrogen fulvestrant significantly halted the growth of HR + /HER2 + cancer cells in vitro and trastuzumab-resistant COH-SC31 as well as trastuzumab-sensitive COH-SC1 tumors in vivo . Conclusions: Compared with the standard trastuzumab treatment, this study demonstrates alternative therapeutic strategies against HR + /HER2 + tumors through establishment of two PDXs coupled with integrative omics analyses and in vivo drug efficacy examination. This work presents a prototype of future "co-clinical" trials to tailor personalized medicine in clinical practice. Clin Cancer Res; 24(2); 395–406. ©2017 AACR .
Hsu, P.-Y., Wu, V. S., Kanaya, N., Petrossian, K., Hsu, H.-K., Nguyen, D., Schmolze, D., Kai, M., Liu, C.-Y., Lu, H., Chu, P., Vito, C. A., Kruper, L., Mortimer, J., Chen, S.
The American Association for Cancer Research (AACR)
1078-0432
10780432
1557-3265
15573265
shingle_title_1 Dual mTOR Kinase Inhibitor MLN0128 Sensitizes HR+/HER2+ Breast Cancer Patient-Derived Xenografts to Trastuzumab or Fulvestrant
shingle_title_2 Dual mTOR Kinase Inhibitor MLN0128 Sensitizes HR+/HER2+ Breast Cancer Patient-Derived Xenografts to Trastuzumab or Fulvestrant
shingle_title_3 Dual mTOR Kinase Inhibitor MLN0128 Sensitizes HR+/HER2+ Breast Cancer Patient-Derived Xenografts to Trastuzumab or Fulvestrant
shingle_title_4 Dual mTOR Kinase Inhibitor MLN0128 Sensitizes HR+/HER2+ Breast Cancer Patient-Derived Xenografts to Trastuzumab or Fulvestrant
timestamp 2025-06-30T23:32:04.178Z
titel Dual mTOR Kinase Inhibitor MLN0128 Sensitizes HR+/HER2+ Breast Cancer Patient-Derived Xenografts to Trastuzumab or Fulvestrant
titel_suche Dual mTOR Kinase Inhibitor MLN0128 Sensitizes HR+/HER2+ Breast Cancer Patient-Derived Xenografts to Trastuzumab or Fulvestrant
topic WW-YZ
uid ipn_articles_6139904