Osimertinib and anti-HER3 combination therapy engages immune dependent tumor toxicity via STING activation in trans

Jose Vicencio Bustamante; Rachel Evans; R Green; Z An; Jinhai Deng; Conor Treacy; Rami Mustapha; James Monypenny of Pitmilly; C Costoya; K Lawler; K Ng; Karen Desouza; O Coban; V Gomez; J Clancy; SH Chen; A Chalk; F Wong; P Gordon; Courtney Savage; C Gomes; T Pan; Giovanna Alfano; Luigi Dolcetti; Julie Nuo En Chan; F Florez-Borja; Paul Barber; Gregory Weitsman; D Sosnowska; E Capone; S Iacobelli; D Hochhauser; J Hartley; Madeline Parsons; James Arnold; Simon Ameer-Beg; Sergio A Quezada; Yosef Yarden; G Sala; Tony Ng

doi:10.1038/s41419-022-04701-3

Osimertinib and anti-HER3 combination therapy engages immune dependent tumor toxicity via STING activation in trans

Jose Vicencio Bustamante^*, Rachel Evans, R Green, Z An, Jinhai Deng, Conor Treacy, Rami Mustapha, James Monypenny of Pitmilly, C Costoya , K Lawler, K Ng, Karen Desouza, O Coban, V Gomez, J Clancy, SH Chen, A Chalk, F Wong, P Gordon, Courtney SavageC Gomes, T Pan, Giovanna Alfano, Luigi Dolcetti, Julie Nuo En Chan, F Florez-Borja , Paul Barber, Gregory Weitsman, D Sosnowska, E Capone, S Iacobelli, D Hochhauser, J Hartley, Madeline Parsons, James Arnold, Simon Ameer-Beg, Sergio A Quezada, Yosef Yarden, G Sala, Tony Ng

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Over the past decade, immunotherapy delivered novel treatments for many cancer types. However, lung cancer still leads cancer mortality, and non-small-cell lung carcinoma patients with mutant EGFR cannot benefit from checkpoint inhibitors due to toxicity, relying only on palliative chemotherapy and the third-generation tyrosine kinase inhibitor (TKI) osimertinib. This new drug extends lifespan by 9-months vs. second-generation TKIs, but unfortunately, cancers relapse due to resistance mechanisms and the lack of antitumor immune responses. Here we explored the combination of osimertinib with anti-HER3 monoclonal antibodies and observed that the immune system contributed to eliminate tumor cells in mice and co-culture experiments using bone marrow-derived macrophages and human PBMCs. Osimertinib led to apoptosis of tumors but simultaneously, it triggered inositol-requiring-enzyme (IRE1α)-dependent HER3 upregulation, increased macrophage infiltration, and activated cGAS in cancer cells to produce cGAMP (detected by a lentivirally transduced STING activity biosensor), transactivating STING in macrophages. We sought to target osimertinib-induced HER3 upregulation with monoclonal antibodies, which engaged Fc receptor-dependent tumor elimination by macrophages, and STING agonists enhanced macrophage-mediated tumor elimination further. Thus, by engaging a tumor non-autonomous mechanism involving cGAS-STING and innate immunity, the combination of osimertinib and anti-HER3 antibodies could improve the limited therapeutic and stratification options for advanced stage lung cancer patients with mutant EGFR.

Original language	English
Article number	274
Journal	Cell Death & Disease
Volume	13
Issue number	3
Early online date	28 Mar 2022
DOIs	https://doi.org/10.1038/s41419-022-04701-3
Publication status	Published - 28 Mar 2022

Keywords

Acrylamides
Aniline Compounds/pharmacology
Animals
Antibodies, Monoclonal/pharmacology
Carcinoma, Non-Small-Cell Lung/drug therapy
Cell Line, Tumor
Drug Resistance, Neoplasm
Endoribonucleases
ErbB Receptors/genetics
Humans
Lung Neoplasms/drug therapy
Mice
Mutation
Neoplasm Recurrence, Local/drug therapy
Nucleotidyltransferases
Protein Kinase Inhibitors/pharmacology
Protein Serine-Threonine Kinases

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41419-022-04701-3Licence: CC BY

Osimertinib and anti-HER3_VICENCIO_Publishedonline28March2022_GOLD VoR (CC BY)Final published version, 4.33 MBLicence: CC BY

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Vicencio Bustamante, J., Evans, R., Green, R., An, Z., Deng, J., Treacy, C., Mustapha, R., Monypenny of Pitmilly, J., Costoya , C., Lawler, K., Ng, K., Desouza, K., Coban, O., Gomez, V., Clancy, J., Chen, SH., Chalk, A., Wong, F., Gordon, P., ... Ng, T. (2022). Osimertinib and anti-HER3 combination therapy engages immune dependent tumor toxicity via STING activation in trans. Cell Death & Disease, 13(3), [274 ]. https://doi.org/10.1038/s41419-022-04701-3

@article{70290495d3984ee59874899d4478a7e2,

title = "Osimertinib and anti-HER3 combination therapy engages immune dependent tumor toxicity via STING activation in trans",

abstract = "Over the past decade, immunotherapy delivered novel treatments for many cancer types. However, lung cancer still leads cancer mortality, and non-small-cell lung carcinoma patients with mutant EGFR cannot benefit from checkpoint inhibitors due to toxicity, relying only on palliative chemotherapy and the third-generation tyrosine kinase inhibitor (TKI) osimertinib. This new drug extends lifespan by 9-months vs. second-generation TKIs, but unfortunately, cancers relapse due to resistance mechanisms and the lack of antitumor immune responses. Here we explored the combination of osimertinib with anti-HER3 monoclonal antibodies and observed that the immune system contributed to eliminate tumor cells in mice and co-culture experiments using bone marrow-derived macrophages and human PBMCs. Osimertinib led to apoptosis of tumors but simultaneously, it triggered inositol-requiring-enzyme (IRE1α)-dependent HER3 upregulation, increased macrophage infiltration, and activated cGAS in cancer cells to produce cGAMP (detected by a lentivirally transduced STING activity biosensor), transactivating STING in macrophages. We sought to target osimertinib-induced HER3 upregulation with monoclonal antibodies, which engaged Fc receptor-dependent tumor elimination by macrophages, and STING agonists enhanced macrophage-mediated tumor elimination further. Thus, by engaging a tumor non-autonomous mechanism involving cGAS-STING and innate immunity, the combination of osimertinib and anti-HER3 antibodies could improve the limited therapeutic and stratification options for advanced stage lung cancer patients with mutant EGFR.",

keywords = "Acrylamides, Aniline Compounds/pharmacology, Animals, Antibodies, Monoclonal/pharmacology, Carcinoma, Non-Small-Cell Lung/drug therapy, Cell Line, Tumor, Drug Resistance, Neoplasm, Endoribonucleases, ErbB Receptors/genetics, Humans, Lung Neoplasms/drug therapy, Mice, Mutation, Neoplasm Recurrence, Local/drug therapy, Nucleotidyltransferases, Protein Kinase Inhibitors/pharmacology, Protein Serine-Threonine Kinases",

author = "{Vicencio Bustamante}, Jose and Rachel Evans and R Green and Z An and Jinhai Deng and Conor Treacy and Rami Mustapha and {Monypenny of Pitmilly}, James and C Costoya and K Lawler and K Ng and Karen Desouza and O Coban and V Gomez and J Clancy and SH Chen and A Chalk and F Wong and P Gordon and Courtney Savage and C Gomes and T Pan and Giovanna Alfano and Luigi Dolcetti and Chan, {Julie Nuo En} and F Florez-Borja and Paul Barber and Gregory Weitsman and D Sosnowska and E Capone and S Iacobelli and D Hochhauser and J Hartley and Madeline Parsons and James Arnold and Simon Ameer-Beg and Quezada, {Sergio A} and Yosef Yarden and G Sala and Tony Ng",

note = "Funding Information: We thank the Woodward laboratory for their kind donation of BioSTING. We thank Dr. Maria Lioumi (KCL) for strategic R&D management. We thank Dr. George Morrow (UCL, Cancer Institute, Flow Cytometry Core Facility) and Leanne Farnan (KCL, Guy?s & St. Thomas? NHS Foundation Trust, Flow Core Facility) for expert assistance with cell sorting equipment. This work was funded by a grant from Astra Zeneca (2015-7, JV, 10029191). This work was also supported by Cancer Research UK funding support to KCL/UCL Comprehensive Cancer Imaging Centre (CRUK & EPSRC, C1519/A16463; for KL, RE, and OC), Cancer Research UK King?s Health Partners Centre at King?s College London (RE and RM, C604/A25135), and Cancer Research UK UCL Centre (PRB, C7675/A29313); as well as CRUK City of London Centre (VG and CG, C7893/A26233). KN was supported by Cancer Research UK Clinical Training Fellowships (176885). LD is supported by EU IMI2 IMMUCAN (RE15612). JV and GA are supported by a CRUK Early Detection and Diagnosis Committee Project grant (C1519/A27375). CS and KD are supported by CRUK National Cancer Imaging Translational Accelerator grant (C1519/A28682). ZA and PG were supported by KCL Breast Cancer Now Research Unit grant. JNA holds a grant from CRUK (DCRPGF\100009) and a Cancer Research Institute/Wade FB Thompson CLIP grant (CRI3645). DS holds a CRUK Ph.D. studentship (C604/A27442). Funding Information: We thank the Woodward laboratory for their kind donation of BioSTING. We thank Dr. Maria Lioumi (KCL) for strategic R&D management. We thank Dr. George Morrow (UCL, Cancer Institute, Flow Cytometry Core Facility) and Leanne Farnan (KCL, Guy{\textquoteright}s & St. Thomas{\textquoteright} NHS Foundation Trust, Flow Core Facility) for expert assistance with cell sorting equipment. This work was funded by a grant from Astra Zeneca (2015-7, JV, 10029191). This work was also supported by Cancer Research UK funding support to KCL/UCL Comprehensive Cancer Imaging Centre (CRUK & EPSRC, C1519/A16463; for KL, RE, and OC), Cancer Research UK King{\textquoteright}s Health Partners Centre at King{\textquoteright}s College London (RE and RM, C604/A25135), and Cancer Research UK UCL Centre (PRB, C7675/A29313); as well as CRUK City of London Centre (VG and CG, C7893/A26233). KN was supported by Cancer Research UK Clinical Training Fellowships (176885). LD is supported by EU IMI2 IMMUCAN (RE15612). JV and GA are supported by a CRUK Early Detection and Diagnosis Committee Project grant (C1519/A27375). CS and KD are supported by CRUK National Cancer Imaging Translational Accelerator grant (C1519/A28682). ZA and PG were supported by KCL Breast Cancer Now Research Unit grant. JNA holds a grant from CRUK (DCRPGF\100009) and a Cancer Research Institute/Wade FB Thompson CLIP grant (CRI3645). DS holds a CRUK Ph.D. studentship (C604/A27442). Publisher Copyright: {\textcopyright} 2022, The Author(s).",

year = "2022",

month = mar,

day = "28",

doi = "10.1038/s41419-022-04701-3",

language = "English",

volume = "13",

journal = "Cell Death & Disease",

issn = "2041-4889",

publisher = "Nature Publishing Group",

number = "3",

}

Vicencio Bustamante, J , Evans, R, Green, R, An, Z , Deng, J , Treacy, C , Mustapha, R , Monypenny of Pitmilly, J, Costoya , C, Lawler, K, Ng, K, Desouza, K , Coban, O, Gomez, V, Clancy, J, Chen, SH, Chalk, A, Wong, F, Gordon, P, Savage, C, Gomes, C, Pan, T, Alfano, G , Dolcetti, L , Chan, JNE, Florez-Borja , F, Barber, P , Weitsman, G, Sosnowska, D, Capone, E, Iacobelli, S, Hochhauser, D, Hartley, J, Parsons, M , Arnold, J , Ameer-Beg, S, Quezada, SA, Yarden, Y, Sala, G & Ng, T 2022, 'Osimertinib and anti-HER3 combination therapy engages immune dependent tumor toxicity via STING activation in trans', Cell Death & Disease, vol. 13, no. 3, 274 . https://doi.org/10.1038/s41419-022-04701-3

TY - JOUR

T1 - Osimertinib and anti-HER3 combination therapy engages immune dependent tumor toxicity via STING activation in trans

AU - Vicencio Bustamante, Jose

AU - Evans, Rachel

AU - Green, R

AU - An, Z

AU - Deng, Jinhai

AU - Treacy, Conor

AU - Mustapha, Rami

AU - Monypenny of Pitmilly, James

AU - Costoya , C

AU - Lawler, K

AU - Ng, K

AU - Desouza, Karen

AU - Coban, O

AU - Gomez, V

AU - Clancy, J

AU - Chen, SH

AU - Chalk, A

AU - Wong, F

AU - Gordon, P

AU - Savage, Courtney

AU - Gomes, C

AU - Pan, T

AU - Alfano, Giovanna

AU - Dolcetti, Luigi

AU - Chan, Julie Nuo En

AU - Florez-Borja , F

AU - Barber, Paul

AU - Weitsman, Gregory

AU - Sosnowska, D

AU - Capone, E

AU - Iacobelli, S

AU - Hochhauser, D

AU - Hartley, J

AU - Parsons, Madeline

AU - Arnold, James

AU - Ameer-Beg, Simon

AU - Quezada, Sergio A

AU - Yarden, Yosef

AU - Sala, G

AU - Ng, Tony

N1 - Funding Information: We thank the Woodward laboratory for their kind donation of BioSTING. We thank Dr. Maria Lioumi (KCL) for strategic R&D management. We thank Dr. George Morrow (UCL, Cancer Institute, Flow Cytometry Core Facility) and Leanne Farnan (KCL, Guy?s & St. Thomas? NHS Foundation Trust, Flow Core Facility) for expert assistance with cell sorting equipment. This work was funded by a grant from Astra Zeneca (2015-7, JV, 10029191). This work was also supported by Cancer Research UK funding support to KCL/UCL Comprehensive Cancer Imaging Centre (CRUK & EPSRC, C1519/A16463; for KL, RE, and OC), Cancer Research UK King?s Health Partners Centre at King?s College London (RE and RM, C604/A25135), and Cancer Research UK UCL Centre (PRB, C7675/A29313); as well as CRUK City of London Centre (VG and CG, C7893/A26233). KN was supported by Cancer Research UK Clinical Training Fellowships (176885). LD is supported by EU IMI2 IMMUCAN (RE15612). JV and GA are supported by a CRUK Early Detection and Diagnosis Committee Project grant (C1519/A27375). CS and KD are supported by CRUK National Cancer Imaging Translational Accelerator grant (C1519/A28682). ZA and PG were supported by KCL Breast Cancer Now Research Unit grant. JNA holds a grant from CRUK (DCRPGF\100009) and a Cancer Research Institute/Wade FB Thompson CLIP grant (CRI3645). DS holds a CRUK Ph.D. studentship (C604/A27442). Funding Information: We thank the Woodward laboratory for their kind donation of BioSTING. We thank Dr. Maria Lioumi (KCL) for strategic R&D management. We thank Dr. George Morrow (UCL, Cancer Institute, Flow Cytometry Core Facility) and Leanne Farnan (KCL, Guy’s & St. Thomas’ NHS Foundation Trust, Flow Core Facility) for expert assistance with cell sorting equipment. This work was funded by a grant from Astra Zeneca (2015-7, JV, 10029191). This work was also supported by Cancer Research UK funding support to KCL/UCL Comprehensive Cancer Imaging Centre (CRUK & EPSRC, C1519/A16463; for KL, RE, and OC), Cancer Research UK King’s Health Partners Centre at King’s College London (RE and RM, C604/A25135), and Cancer Research UK UCL Centre (PRB, C7675/A29313); as well as CRUK City of London Centre (VG and CG, C7893/A26233). KN was supported by Cancer Research UK Clinical Training Fellowships (176885). LD is supported by EU IMI2 IMMUCAN (RE15612). JV and GA are supported by a CRUK Early Detection and Diagnosis Committee Project grant (C1519/A27375). CS and KD are supported by CRUK National Cancer Imaging Translational Accelerator grant (C1519/A28682). ZA and PG were supported by KCL Breast Cancer Now Research Unit grant. JNA holds a grant from CRUK (DCRPGF\100009) and a Cancer Research Institute/Wade FB Thompson CLIP grant (CRI3645). DS holds a CRUK Ph.D. studentship (C604/A27442). Publisher Copyright: © 2022, The Author(s).

PY - 2022/3/28

Y1 - 2022/3/28

N2 - Over the past decade, immunotherapy delivered novel treatments for many cancer types. However, lung cancer still leads cancer mortality, and non-small-cell lung carcinoma patients with mutant EGFR cannot benefit from checkpoint inhibitors due to toxicity, relying only on palliative chemotherapy and the third-generation tyrosine kinase inhibitor (TKI) osimertinib. This new drug extends lifespan by 9-months vs. second-generation TKIs, but unfortunately, cancers relapse due to resistance mechanisms and the lack of antitumor immune responses. Here we explored the combination of osimertinib with anti-HER3 monoclonal antibodies and observed that the immune system contributed to eliminate tumor cells in mice and co-culture experiments using bone marrow-derived macrophages and human PBMCs. Osimertinib led to apoptosis of tumors but simultaneously, it triggered inositol-requiring-enzyme (IRE1α)-dependent HER3 upregulation, increased macrophage infiltration, and activated cGAS in cancer cells to produce cGAMP (detected by a lentivirally transduced STING activity biosensor), transactivating STING in macrophages. We sought to target osimertinib-induced HER3 upregulation with monoclonal antibodies, which engaged Fc receptor-dependent tumor elimination by macrophages, and STING agonists enhanced macrophage-mediated tumor elimination further. Thus, by engaging a tumor non-autonomous mechanism involving cGAS-STING and innate immunity, the combination of osimertinib and anti-HER3 antibodies could improve the limited therapeutic and stratification options for advanced stage lung cancer patients with mutant EGFR.

AB - Over the past decade, immunotherapy delivered novel treatments for many cancer types. However, lung cancer still leads cancer mortality, and non-small-cell lung carcinoma patients with mutant EGFR cannot benefit from checkpoint inhibitors due to toxicity, relying only on palliative chemotherapy and the third-generation tyrosine kinase inhibitor (TKI) osimertinib. This new drug extends lifespan by 9-months vs. second-generation TKIs, but unfortunately, cancers relapse due to resistance mechanisms and the lack of antitumor immune responses. Here we explored the combination of osimertinib with anti-HER3 monoclonal antibodies and observed that the immune system contributed to eliminate tumor cells in mice and co-culture experiments using bone marrow-derived macrophages and human PBMCs. Osimertinib led to apoptosis of tumors but simultaneously, it triggered inositol-requiring-enzyme (IRE1α)-dependent HER3 upregulation, increased macrophage infiltration, and activated cGAS in cancer cells to produce cGAMP (detected by a lentivirally transduced STING activity biosensor), transactivating STING in macrophages. We sought to target osimertinib-induced HER3 upregulation with monoclonal antibodies, which engaged Fc receptor-dependent tumor elimination by macrophages, and STING agonists enhanced macrophage-mediated tumor elimination further. Thus, by engaging a tumor non-autonomous mechanism involving cGAS-STING and innate immunity, the combination of osimertinib and anti-HER3 antibodies could improve the limited therapeutic and stratification options for advanced stage lung cancer patients with mutant EGFR.

KW - Acrylamides

KW - Aniline Compounds/pharmacology

KW - Animals

KW - Antibodies, Monoclonal/pharmacology

KW - Carcinoma, Non-Small-Cell Lung/drug therapy

KW - Cell Line, Tumor

KW - Drug Resistance, Neoplasm

KW - Endoribonucleases

KW - ErbB Receptors/genetics

KW - Humans

KW - Lung Neoplasms/drug therapy

KW - Mice

KW - Mutation

KW - Neoplasm Recurrence, Local/drug therapy

KW - Nucleotidyltransferases

KW - Protein Kinase Inhibitors/pharmacology

KW - Protein Serine-Threonine Kinases

UR - http://www.scopus.com/inward/record.url?scp=85127235626&partnerID=8YFLogxK

U2 - 10.1038/s41419-022-04701-3

DO - 10.1038/s41419-022-04701-3

M3 - Article

C2 - 35347108

SN - 2041-4889

VL - 13

JO - Cell Death & Disease

JF - Cell Death & Disease

IS - 3

M1 - 274

ER -

Osimertinib and anti-HER3 combination therapy engages immune dependent tumor toxicity via STING activation in trans

Abstract

Keywords

UN SDGs

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