A novel proteotoxic combination therapy for EGFR+ and HER2+ cancers

Mengxiong Wang, Renan B. Ferreira, Mary E. Law, Bradley J. Davis, Elham Yaaghubi, Amanda F. Ghilardi, Abhisheak Sharma, Bonnie A. Avery, Edgardo Rodriguez, Chi-Wu Chiang, Satya Narayan, Coy D. Heldermon, Ronald K. Castellano, Brian K. Law

Research output: Contribution to journalArticle

Abstract

While HER2 and EGFR are overexpressed in breast cancers and multiple other types of tumors, the use of EGFR and/or HER2 inhibitors have failed to cure many cancer patients, largely because cancers acquire resistance to HER2/EGFR-specific drugs. Cancers that overexpress the HER-family proteins EGFR, HER2, and HER3 are uniquely sensitive to agents that disrupt HER2 and EGFR protein folding. We previously showed that disruption of disulfide bond formation by Disulfide Disrupting Agents (DDAs) kills HER2/EGFR overexpressing cells through multiple mechanisms. Herein, we show that interference with proline isomerization in HER2/EGFR overexpressing cells also induces cancer cell death. The peptidyl-prolyl isomerase inhibitor Cyclosporine A (CsA) selectively kills EGFR+ or HER2+ breast cancer cells in vitro by activating caspase-dependent apoptotic pathways. Further, CsA synergizes with the DDA tcyDTDO to kill HER2/EGFR overexpressing cells in vitro and the two agents cooperate to kill HER2+ tumors in vivo. There is a critical need for novel strategies to target HER2+ and EGFR+ cancers that are resistant to currently available mechanism-based agents. Drugs that target HER2/EGFR protein folding, including DDAs and CsA, have the potential to kill cancers that overexpress EGFR or HER2 through the induction of proteostatic synthetic lethality.

Original languageEnglish
Pages (from-to)4264-4282
Number of pages19
JournalOncogene
Volume38
Issue number22
DOIs
Publication statusPublished - 2019 May 30

Fingerprint

Disulfides
Neoplasms
Cyclosporine
Protein Folding
Therapeutics
Peptidylprolyl Isomerase
Breast Neoplasms
Caspases
Proline
Pharmaceutical Preparations
Cell Death
Proteins
In Vitro Techniques

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Wang, M., Ferreira, R. B., Law, M. E., Davis, B. J., Yaaghubi, E., Ghilardi, A. F., ... Law, B. K. (2019). A novel proteotoxic combination therapy for EGFR+ and HER2+ cancers. Oncogene, 38(22), 4264-4282. https://doi.org/10.1038/s41388-019-0717-6
Wang, Mengxiong ; Ferreira, Renan B. ; Law, Mary E. ; Davis, Bradley J. ; Yaaghubi, Elham ; Ghilardi, Amanda F. ; Sharma, Abhisheak ; Avery, Bonnie A. ; Rodriguez, Edgardo ; Chiang, Chi-Wu ; Narayan, Satya ; Heldermon, Coy D. ; Castellano, Ronald K. ; Law, Brian K. / A novel proteotoxic combination therapy for EGFR+ and HER2+ cancers. In: Oncogene. 2019 ; Vol. 38, No. 22. pp. 4264-4282.
@article{6772d9b4a2074588b943baedfd3fb7c7,
title = "A novel proteotoxic combination therapy for EGFR+ and HER2+ cancers",
abstract = "While HER2 and EGFR are overexpressed in breast cancers and multiple other types of tumors, the use of EGFR and/or HER2 inhibitors have failed to cure many cancer patients, largely because cancers acquire resistance to HER2/EGFR-specific drugs. Cancers that overexpress the HER-family proteins EGFR, HER2, and HER3 are uniquely sensitive to agents that disrupt HER2 and EGFR protein folding. We previously showed that disruption of disulfide bond formation by Disulfide Disrupting Agents (DDAs) kills HER2/EGFR overexpressing cells through multiple mechanisms. Herein, we show that interference with proline isomerization in HER2/EGFR overexpressing cells also induces cancer cell death. The peptidyl-prolyl isomerase inhibitor Cyclosporine A (CsA) selectively kills EGFR+ or HER2+ breast cancer cells in vitro by activating caspase-dependent apoptotic pathways. Further, CsA synergizes with the DDA tcyDTDO to kill HER2/EGFR overexpressing cells in vitro and the two agents cooperate to kill HER2+ tumors in vivo. There is a critical need for novel strategies to target HER2+ and EGFR+ cancers that are resistant to currently available mechanism-based agents. Drugs that target HER2/EGFR protein folding, including DDAs and CsA, have the potential to kill cancers that overexpress EGFR or HER2 through the induction of proteostatic synthetic lethality.",
author = "Mengxiong Wang and Ferreira, {Renan B.} and Law, {Mary E.} and Davis, {Bradley J.} and Elham Yaaghubi and Ghilardi, {Amanda F.} and Abhisheak Sharma and Avery, {Bonnie A.} and Edgardo Rodriguez and Chi-Wu Chiang and Satya Narayan and Heldermon, {Coy D.} and Castellano, {Ronald K.} and Law, {Brian K.}",
year = "2019",
month = "5",
day = "30",
doi = "10.1038/s41388-019-0717-6",
language = "English",
volume = "38",
pages = "4264--4282",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "22",

}

Wang, M, Ferreira, RB, Law, ME, Davis, BJ, Yaaghubi, E, Ghilardi, AF, Sharma, A, Avery, BA, Rodriguez, E, Chiang, C-W, Narayan, S, Heldermon, CD, Castellano, RK & Law, BK 2019, 'A novel proteotoxic combination therapy for EGFR+ and HER2+ cancers', Oncogene, vol. 38, no. 22, pp. 4264-4282. https://doi.org/10.1038/s41388-019-0717-6

A novel proteotoxic combination therapy for EGFR+ and HER2+ cancers. / Wang, Mengxiong; Ferreira, Renan B.; Law, Mary E.; Davis, Bradley J.; Yaaghubi, Elham; Ghilardi, Amanda F.; Sharma, Abhisheak; Avery, Bonnie A.; Rodriguez, Edgardo; Chiang, Chi-Wu; Narayan, Satya; Heldermon, Coy D.; Castellano, Ronald K.; Law, Brian K.

In: Oncogene, Vol. 38, No. 22, 30.05.2019, p. 4264-4282.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A novel proteotoxic combination therapy for EGFR+ and HER2+ cancers

AU - Wang, Mengxiong

AU - Ferreira, Renan B.

AU - Law, Mary E.

AU - Davis, Bradley J.

AU - Yaaghubi, Elham

AU - Ghilardi, Amanda F.

AU - Sharma, Abhisheak

AU - Avery, Bonnie A.

AU - Rodriguez, Edgardo

AU - Chiang, Chi-Wu

AU - Narayan, Satya

AU - Heldermon, Coy D.

AU - Castellano, Ronald K.

AU - Law, Brian K.

PY - 2019/5/30

Y1 - 2019/5/30

N2 - While HER2 and EGFR are overexpressed in breast cancers and multiple other types of tumors, the use of EGFR and/or HER2 inhibitors have failed to cure many cancer patients, largely because cancers acquire resistance to HER2/EGFR-specific drugs. Cancers that overexpress the HER-family proteins EGFR, HER2, and HER3 are uniquely sensitive to agents that disrupt HER2 and EGFR protein folding. We previously showed that disruption of disulfide bond formation by Disulfide Disrupting Agents (DDAs) kills HER2/EGFR overexpressing cells through multiple mechanisms. Herein, we show that interference with proline isomerization in HER2/EGFR overexpressing cells also induces cancer cell death. The peptidyl-prolyl isomerase inhibitor Cyclosporine A (CsA) selectively kills EGFR+ or HER2+ breast cancer cells in vitro by activating caspase-dependent apoptotic pathways. Further, CsA synergizes with the DDA tcyDTDO to kill HER2/EGFR overexpressing cells in vitro and the two agents cooperate to kill HER2+ tumors in vivo. There is a critical need for novel strategies to target HER2+ and EGFR+ cancers that are resistant to currently available mechanism-based agents. Drugs that target HER2/EGFR protein folding, including DDAs and CsA, have the potential to kill cancers that overexpress EGFR or HER2 through the induction of proteostatic synthetic lethality.

AB - While HER2 and EGFR are overexpressed in breast cancers and multiple other types of tumors, the use of EGFR and/or HER2 inhibitors have failed to cure many cancer patients, largely because cancers acquire resistance to HER2/EGFR-specific drugs. Cancers that overexpress the HER-family proteins EGFR, HER2, and HER3 are uniquely sensitive to agents that disrupt HER2 and EGFR protein folding. We previously showed that disruption of disulfide bond formation by Disulfide Disrupting Agents (DDAs) kills HER2/EGFR overexpressing cells through multiple mechanisms. Herein, we show that interference with proline isomerization in HER2/EGFR overexpressing cells also induces cancer cell death. The peptidyl-prolyl isomerase inhibitor Cyclosporine A (CsA) selectively kills EGFR+ or HER2+ breast cancer cells in vitro by activating caspase-dependent apoptotic pathways. Further, CsA synergizes with the DDA tcyDTDO to kill HER2/EGFR overexpressing cells in vitro and the two agents cooperate to kill HER2+ tumors in vivo. There is a critical need for novel strategies to target HER2+ and EGFR+ cancers that are resistant to currently available mechanism-based agents. Drugs that target HER2/EGFR protein folding, including DDAs and CsA, have the potential to kill cancers that overexpress EGFR or HER2 through the induction of proteostatic synthetic lethality.

UR - http://www.scopus.com/inward/record.url?scp=85061063496&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85061063496&partnerID=8YFLogxK

U2 - 10.1038/s41388-019-0717-6

DO - 10.1038/s41388-019-0717-6

M3 - Article

VL - 38

SP - 4264

EP - 4282

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 22

ER -

Wang M, Ferreira RB, Law ME, Davis BJ, Yaaghubi E, Ghilardi AF et al. A novel proteotoxic combination therapy for EGFR+ and HER2+ cancers. Oncogene. 2019 May 30;38(22):4264-4282. https://doi.org/10.1038/s41388-019-0717-6