King's College London

Research portal

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

Research output: Contribution to journalArticlepeer-review

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 & 20 more 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

Original languageEnglish
Article number274
JournalCell Death & Disease
Volume13
Issue number3
Early online date28 Mar 2022
DOIs
Accepted/In press1 Mar 2022
E-pub ahead of print28 Mar 2022
Published28 Mar 2022

Bibliographical 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’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).

Documents

King's Authors

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.

View graph of relations

© 2020 King's College London | Strand | London WC2R 2LS | England | United Kingdom | Tel +44 (0)20 7836 5454