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.

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. - ISSN 1541-7786. - 17:11(2019), p. 2318-2330. [10.1158/1541-7786.MCR-19-0756]

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

DE ANGELIS, CARMINE
Secondo
;
2019

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.
2019
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. - ISSN 1541-7786. - 17:11(2019), p. 2318-2330. [10.1158/1541-7786.MCR-19-0756]
File in questo prodotto:
Non ci sono file associati a questo prodotto.

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/776669
Citazioni
  • ???jsp.display-item.citation.pmc??? ND
  • Scopus 40
  • ???jsp.display-item.citation.isi??? 35
social impact