Targeting the Mevalonate Pathway to Overcome Acquired Anti-HER2 Treatment Resistance in Breast Cancer

Vidyalakshmi Sethunath, Huizhong Hu, Carmine De Angelis, Jamunarani Veeraraghavan, Lanfang Qin, Nicholas Wang, Lukas M. Simon, Tao Wang, Xiaoyong Fu, Agostina Nardone, Resel Pereira, Sarmistha Nanda, Obi L. Griffith, Anna Tsimelzon, Chad Shaw, Gary C. Chamness, Jorge S. Reis-Filho, Britta Weigelt, Laura M. Heiser, Susan G. HilsenbeckShixia Huang, Mothaffar F. Rimawi, Joe W. Gray, C. Kent Osborne, Rachel Schiff

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Despite effective strategies, resistance in HER2+ breast cancer remains a challenge. While the mevalonate pathway (MVA) is suggested to promote cell growth and survival, including in HER2+ models, its potential role in resistance to HER2-targeted therapy is unknown. Parental HER2+ breast cancer cells and their lapatinib-resistant and lapatinib + trastuzumab-resistant derivatives were used for this study. MVA activity was found to be increased in lapatinib-resistant and lapatinib + trastuzumab-resistant cells. Specific blockade of this pathway with lipophilic but not hydrophilic statins and with the N-bisphosphonate zoledronic acid led to apoptosis and substantial growth inhibition of R cells. Inhibition was rescued by mevalonate or the intermediate metabolites farnesyl pyrophosphate or geranylgeranyl pyrophosphate, but not cholesterol. Activated Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) and mTORC1 signaling, and their downstream target gene product Survivin, were inhibited by MVA blockade, especially in the lapatinib-resistant/lapatinib + trastuzumab-resistant models. Overexpression of constitutively active YAP rescued Survivin and phosphorylated-S6 levels, despite blockade of the MVA. These results suggest that the MVA provides alternative signaling leading to cell survival and resistance by activating YAP/TAZ-mTORC1-Survivin signaling when HER2 is blocked, suggesting novel therapeutic targets. MVA inhibitors including lipophilic statins and N-bisphosphonates may circumvent resistance to anti-HER2 therapy warranting further clinical investigation. IMPLICATIONS: The MVA was found to constitute an escape mechanism of survival and growth in HER2+ breast cancer models resistant to anti-HER2 therapies. MVA inhibitors such as simvastatin and zoledronic acid are potential therapeutic agents to resensitize the tumors that depend on the MVA to progress on anti-HER2 therapies.

Original languageEnglish (US)
Pages (from-to)2318-2330
Number of pages13
JournalMolecular cancer research : MCR
Volume17
Issue number11
DOIs
StatePublished - Nov 1 2019

Fingerprint

Mevalonic Acid
Breast Neoplasms
zoledronic acid
Hydroxymethylglutaryl-CoA Reductase Inhibitors
simvastatin acid
Diphosphonates
Cell Survival
Therapeutics
Growth
S 6
Proteins
lapatinib
Cholesterol
Apoptosis

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Sethunath, V., Hu, H., De Angelis, C., Veeraraghavan, J., Qin, L., Wang, N., ... Schiff, R. (2019). Targeting the Mevalonate Pathway to Overcome Acquired Anti-HER2 Treatment Resistance in Breast Cancer. Molecular cancer research : MCR, 17(11), 2318-2330. https://doi.org/10.1158/1541-7786.MCR-19-0756

Targeting the Mevalonate Pathway to Overcome Acquired Anti-HER2 Treatment Resistance in Breast Cancer. / Sethunath, Vidyalakshmi; Hu, Huizhong; De Angelis, Carmine; Veeraraghavan, Jamunarani; Qin, Lanfang; Wang, Nicholas; Simon, Lukas M.; Wang, Tao; Fu, Xiaoyong; Nardone, Agostina; Pereira, Resel; Nanda, Sarmistha; Griffith, Obi L.; Tsimelzon, Anna; Shaw, Chad; Chamness, Gary C.; Reis-Filho, Jorge S.; Weigelt, Britta; Heiser, Laura M.; Hilsenbeck, Susan G.; Huang, Shixia; Rimawi, Mothaffar F.; Gray, Joe W.; Osborne, C. Kent; Schiff, Rachel.

In: Molecular cancer research : MCR, Vol. 17, No. 11, 01.11.2019, p. 2318-2330.

Research output: Contribution to journalArticle

Sethunath, V, Hu, H, De Angelis, C, Veeraraghavan, J, Qin, L, Wang, N, Simon, LM, Wang, T, Fu, X, Nardone, A, Pereira, R, Nanda, S, Griffith, OL, Tsimelzon, A, Shaw, C, Chamness, GC, Reis-Filho, JS, Weigelt, B, Heiser, LM, Hilsenbeck, SG, Huang, S, Rimawi, MF, Gray, JW, Osborne, CK & Schiff, R 2019, 'Targeting the Mevalonate Pathway to Overcome Acquired Anti-HER2 Treatment Resistance in Breast Cancer', Molecular cancer research : MCR, vol. 17, no. 11, pp. 2318-2330. https://doi.org/10.1158/1541-7786.MCR-19-0756
Sethunath, Vidyalakshmi ; Hu, Huizhong ; De Angelis, Carmine ; Veeraraghavan, Jamunarani ; Qin, Lanfang ; Wang, Nicholas ; Simon, Lukas M. ; Wang, Tao ; Fu, Xiaoyong ; Nardone, Agostina ; Pereira, Resel ; Nanda, Sarmistha ; Griffith, Obi L. ; Tsimelzon, Anna ; Shaw, Chad ; Chamness, Gary C. ; Reis-Filho, Jorge S. ; Weigelt, Britta ; Heiser, Laura M. ; Hilsenbeck, Susan G. ; Huang, Shixia ; Rimawi, Mothaffar F. ; Gray, Joe W. ; Osborne, C. Kent ; Schiff, Rachel. / Targeting the Mevalonate Pathway to Overcome Acquired Anti-HER2 Treatment Resistance in Breast Cancer. In: Molecular cancer research : MCR. 2019 ; Vol. 17, No. 11. pp. 2318-2330.
@article{35db7377a2a2412e890d6afe41265851,
title = "Targeting the Mevalonate Pathway to Overcome Acquired Anti-HER2 Treatment Resistance in Breast Cancer",
abstract = "Despite effective strategies, resistance in HER2+ breast cancer remains a challenge. While the mevalonate pathway (MVA) is suggested to promote cell growth and survival, including in HER2+ models, its potential role in resistance to HER2-targeted therapy is unknown. Parental HER2+ breast cancer cells and their lapatinib-resistant and lapatinib + trastuzumab-resistant derivatives were used for this study. MVA activity was found to be increased in lapatinib-resistant and lapatinib + trastuzumab-resistant cells. Specific blockade of this pathway with lipophilic but not hydrophilic statins and with the N-bisphosphonate zoledronic acid led to apoptosis and substantial growth inhibition of R cells. Inhibition was rescued by mevalonate or the intermediate metabolites farnesyl pyrophosphate or geranylgeranyl pyrophosphate, but not cholesterol. Activated Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) and mTORC1 signaling, and their downstream target gene product Survivin, were inhibited by MVA blockade, especially in the lapatinib-resistant/lapatinib + trastuzumab-resistant models. Overexpression of constitutively active YAP rescued Survivin and phosphorylated-S6 levels, despite blockade of the MVA. These results suggest that the MVA provides alternative signaling leading to cell survival and resistance by activating YAP/TAZ-mTORC1-Survivin signaling when HER2 is blocked, suggesting novel therapeutic targets. MVA inhibitors including lipophilic statins and N-bisphosphonates may circumvent resistance to anti-HER2 therapy warranting further clinical investigation. IMPLICATIONS: The MVA was found to constitute an escape mechanism of survival and growth in HER2+ breast cancer models resistant to anti-HER2 therapies. MVA inhibitors such as simvastatin and zoledronic acid are potential therapeutic agents to resensitize the tumors that depend on the MVA to progress on anti-HER2 therapies.",
author = "Vidyalakshmi Sethunath and Huizhong Hu and {De Angelis}, Carmine and Jamunarani Veeraraghavan and Lanfang Qin and Nicholas Wang and Simon, {Lukas M.} and Tao Wang and Xiaoyong Fu and Agostina Nardone and Resel Pereira and Sarmistha Nanda and Griffith, {Obi L.} and Anna Tsimelzon and Chad Shaw and Chamness, {Gary C.} and Reis-Filho, {Jorge S.} and Britta Weigelt and Heiser, {Laura M.} and Hilsenbeck, {Susan G.} and Shixia Huang and Rimawi, {Mothaffar F.} and Gray, {Joe W.} and Osborne, {C. Kent} and Rachel Schiff",
year = "2019",
month = "11",
day = "1",
doi = "10.1158/1541-7786.MCR-19-0756",
language = "English (US)",
volume = "17",
pages = "2318--2330",
journal = "Molecular Cancer Research",
issn = "1541-7786",
publisher = "American Association for Cancer Research Inc.",
number = "11",

}

TY - JOUR

T1 - Targeting the Mevalonate Pathway to Overcome Acquired Anti-HER2 Treatment Resistance in Breast Cancer

AU - Sethunath, Vidyalakshmi

AU - Hu, Huizhong

AU - De Angelis, Carmine

AU - Veeraraghavan, Jamunarani

AU - Qin, Lanfang

AU - Wang, Nicholas

AU - Simon, Lukas M.

AU - Wang, Tao

AU - Fu, Xiaoyong

AU - Nardone, Agostina

AU - Pereira, Resel

AU - Nanda, Sarmistha

AU - Griffith, Obi L.

AU - Tsimelzon, Anna

AU - Shaw, Chad

AU - Chamness, Gary C.

AU - Reis-Filho, Jorge S.

AU - Weigelt, Britta

AU - Heiser, Laura M.

AU - Hilsenbeck, Susan G.

AU - Huang, Shixia

AU - Rimawi, Mothaffar F.

AU - Gray, Joe W.

AU - Osborne, C. Kent

AU - Schiff, Rachel

PY - 2019/11/1

Y1 - 2019/11/1

N2 - Despite effective strategies, resistance in HER2+ breast cancer remains a challenge. While the mevalonate pathway (MVA) is suggested to promote cell growth and survival, including in HER2+ models, its potential role in resistance to HER2-targeted therapy is unknown. Parental HER2+ breast cancer cells and their lapatinib-resistant and lapatinib + trastuzumab-resistant derivatives were used for this study. MVA activity was found to be increased in lapatinib-resistant and lapatinib + trastuzumab-resistant cells. Specific blockade of this pathway with lipophilic but not hydrophilic statins and with the N-bisphosphonate zoledronic acid led to apoptosis and substantial growth inhibition of R cells. Inhibition was rescued by mevalonate or the intermediate metabolites farnesyl pyrophosphate or geranylgeranyl pyrophosphate, but not cholesterol. Activated Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) and mTORC1 signaling, and their downstream target gene product Survivin, were inhibited by MVA blockade, especially in the lapatinib-resistant/lapatinib + trastuzumab-resistant models. Overexpression of constitutively active YAP rescued Survivin and phosphorylated-S6 levels, despite blockade of the MVA. These results suggest that the MVA provides alternative signaling leading to cell survival and resistance by activating YAP/TAZ-mTORC1-Survivin signaling when HER2 is blocked, suggesting novel therapeutic targets. MVA inhibitors including lipophilic statins and N-bisphosphonates may circumvent resistance to anti-HER2 therapy warranting further clinical investigation. IMPLICATIONS: The MVA was found to constitute an escape mechanism of survival and growth in HER2+ breast cancer models resistant to anti-HER2 therapies. MVA inhibitors such as simvastatin and zoledronic acid are potential therapeutic agents to resensitize the tumors that depend on the MVA to progress on anti-HER2 therapies.

AB - Despite effective strategies, resistance in HER2+ breast cancer remains a challenge. While the mevalonate pathway (MVA) is suggested to promote cell growth and survival, including in HER2+ models, its potential role in resistance to HER2-targeted therapy is unknown. Parental HER2+ breast cancer cells and their lapatinib-resistant and lapatinib + trastuzumab-resistant derivatives were used for this study. MVA activity was found to be increased in lapatinib-resistant and lapatinib + trastuzumab-resistant cells. Specific blockade of this pathway with lipophilic but not hydrophilic statins and with the N-bisphosphonate zoledronic acid led to apoptosis and substantial growth inhibition of R cells. Inhibition was rescued by mevalonate or the intermediate metabolites farnesyl pyrophosphate or geranylgeranyl pyrophosphate, but not cholesterol. Activated Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) and mTORC1 signaling, and their downstream target gene product Survivin, were inhibited by MVA blockade, especially in the lapatinib-resistant/lapatinib + trastuzumab-resistant models. Overexpression of constitutively active YAP rescued Survivin and phosphorylated-S6 levels, despite blockade of the MVA. These results suggest that the MVA provides alternative signaling leading to cell survival and resistance by activating YAP/TAZ-mTORC1-Survivin signaling when HER2 is blocked, suggesting novel therapeutic targets. MVA inhibitors including lipophilic statins and N-bisphosphonates may circumvent resistance to anti-HER2 therapy warranting further clinical investigation. IMPLICATIONS: The MVA was found to constitute an escape mechanism of survival and growth in HER2+ breast cancer models resistant to anti-HER2 therapies. MVA inhibitors such as simvastatin and zoledronic acid are potential therapeutic agents to resensitize the tumors that depend on the MVA to progress on anti-HER2 therapies.

UR - http://www.scopus.com/inward/record.url?scp=85074018943&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85074018943&partnerID=8YFLogxK

U2 - 10.1158/1541-7786.MCR-19-0756

DO - 10.1158/1541-7786.MCR-19-0756

M3 - Article

C2 - 31420371

AN - SCOPUS:85074018943

VL - 17

SP - 2318

EP - 2330

JO - Molecular Cancer Research

JF - Molecular Cancer Research

SN - 1541-7786

IS - 11

ER -