A HER2-targeting antibody-MMAE conjugate RC48 sensitizes immunotherapy in HER2-positive colon cancer by triggering the cGAS-STING pathway

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Abstract

Human epidermal growth factor receptor 2 (HER2) is a protein that is overexpressed in some types of cancer, including breast and urothelial cancer. Here we found that HER2 was present in a portion of colon cancer patients, raising the possibility of using anti-HER2 therapy. RC48, a novel antibody-drug conjugate (ADC) comprising cytotoxic monomethyl auristatin E (MMAE) and an anti-HER2 antibody tethered via a linker, showed a comparable therapeutic effect in both HER2 low expressed (IHC2+/FISH- or IHC+) and high expressed urothelial cancer patients. In vitro studies using colon cancer cell lines showed that RC48 effectively impeded the proliferation of HER2-positive cells, indicating its potential as a treatment for HER2-positive colon cancer. Mechanism study showed that RC48 not only induces cell cycle arrest but also disrupts HER2-mediated restain of cGAS-STING signaling, potentially activating an immune response against the cancer cells. The administration of RC48 significantly reduced the growth of HER2-positive colon cancer and made HER2-positive colon cancer cells more susceptible to immunotherapy. The results of our study will contribute to determining the feasibility of RC48 as a therapeutic option for HER2-positive colon cancer.

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Cancer statistics in China and United States, 2022: profiles, trends, and determinants

Changfa Xia, Xuesi Dong, He. Li … (2022)

Background: The cancer burden in the United States of America (USA) has decreased gradually. However, China is experiencing a transition in its cancer profiles, with greater incidence of cancers that were previously more common in the USA. This study compared the latest cancer profiles, trends, and determinants between China and USA. Methods: This was a comparative study using open-source data. Cancer cases and deaths in 2022 were calculated using cancer estimates from GLOBOCAN 2020 and population estimates from the United Nations. Trends in cancer incidence and mortality rates in the USA used data from the Surveillance, Epidemiology, and End Results program and National Center for Health Statistics. Chinese data were obtained from cancer registry reports. Data from the Global Burden of Disease 2019 and a decomposition method were used to express cancer deaths as the product of four determinant factors. Results: In 2022, there will be approximately 4,820,000 and 2,370,000 new cancer cases, and 3,210,000 and 640,000 cancer deaths in China and the USA, respectively. The most common cancers are lung cancer in China and breast cancer in the USA, and lung cancer is the leading cause of cancer death in both. Age-standardized incidence and mortality rates for lung cancer and colorectal cancer in the USA have decreased significantly recently, but rates of liver cancer have increased slightly. Rates of stomach, liver, and esophageal cancer decreased gradually in China, but rates have increased for colorectal cancer in the whole population, prostate cancer in men, and other seven cancer types in women. Increases in adult population size and population aging were major determinants for incremental cancer deaths, and case-fatality rates contributed to reduced cancer deaths in both countries. Conclusions: The decreasing cancer burden in liver, stomach, and esophagus, and increasing burden in lung, colorectum, breast, and prostate, mean that cancer profiles in China and the USA are converging. Population aging is a growing determinant of incremental cancer burden. Progress in cancer prevention and care in the USA, and measures to actively respond to population aging, may help China to reduce the cancer burden.

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ESMO consensus guidelines for the management of patients with metastatic colorectal cancer.

E Van Cutsem, A Cervantes, R. Adam … (2016)

Colorectal cancer (CRC) is one of the most common malignancies in Western countries. Over the last 20 years, and the last decade in particular, the clinical outcome for patients with metastatic CRC (mCRC) has improved greatly due not only to an increase in the number of patients being referred for and undergoing surgical resection of their localised metastatic disease but also to a more strategic approach to the delivery of systemic therapy and an expansion in the use of ablative techniques. This reflects the increase in the number of patients that are being managed within a multidisciplinary team environment and specialist cancer centres, and the emergence over the same time period not only of improved imaging techniques but also prognostic and predictive molecular markers. Treatment decisions for patients with mCRC must be evidence-based. Thus, these ESMO consensus guidelines have been developed based on the current available evidence to provide a series of evidence-based recommendations to assist in the treatment and management of patients with mCRC in this rapidly evolving treatment setting.

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Immunotherapy in colorectal cancer: rationale, challenges and potential

Karuna Ganesh, Zsofia K. Stadler, Andrea Cercek … (2019)

Following initial successes in melanoma treatment, immunotherapy has rapidly become established as a major treatment modality for multiple types of solid cancers, including a subset of colorectal cancers (CRCs). Two programmed cell death 1 (PD1)-blocking antibodies, pembrolizumab and nivolumab, have shown efficacy in patients with metastatic CRC that is mismatch-repair-deficient and microsatellite instability-high (dMMR-MSI-H), and have been granted accelerated FDA approval. In contrast to most other treatments for metastatic cancer, immunotherapy achieves long-term durable remission in a subset of patients, highlighting the tremendous promise of immunotherapy in treating dMMR-MSI-H metastatic CRC. Here, we review the clinical development of immune checkpoint inhibition in CRC leading to regulatory approvals for the treatment of dMMR-MSI-H CRC. We focus on new advances in expanding the efficacy of immunotherapy to early-stage CRC and CRC that is mismatch-repair-proficient and has low microsatellite instability (pMMR-MSI-L) and discuss emerging approaches for targeting the immune microenvironment, which might complement immune checkpoint inhibition.

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Author and article information

Contributors

Wenjie Guo:

ORCID: http://orcid.org/0000-0001-8506-3905

guowj@nju.edu.cn

Wen Liu: liuwen@nju.edu.cn

Yanhong Gu:

ORCID: http://orcid.org/0000-0002-0379-0410

guyhphd@163.com

Journal

Journal ID (nlm-ta): Cell Death Dis

Journal ID (iso-abbrev): Cell Death Dis

Title: Cell Death & Disease

Publisher: Nature Publishing Group UK (London )

ISSN (Electronic): 2041-4889

Publication date (Electronic): 24 August 2023

Publication date PMC-release: 24 August 2023

Publication date Collection: August 2023

Volume: 14

Issue: 8

Electronic Location Identifier: 550

Affiliations

[1 ]GRID grid.412676.0, ISNI 0000 0004 1799 0784, Department of Oncology and Cancer Rehabilitation Centre, , The First Affiliated Hospital of Nanjing Medical University, ; Nanjing, Jiangsu China

[2 ]GRID grid.41156.37, ISNI 0000 0001 2314 964X, State Key Laboratory of Pharmaceutical Biotechnology, Engineering Research Center of Protein and Peptide Medicine, School of Life Sciences, , Nanjing University, ; Nanjing, China

Author information

Wenjie Guo http://orcid.org/0000-0001-8506-3905

Qiang Xu http://orcid.org/0000-0002-3530-9855

Yanhong Gu http://orcid.org/0000-0002-0379-0410

Article

Publisher ID: 6073

DOI: 10.1038/s41419-023-06073-8

PMC ID: 10449775

PubMed ID: 37620320

SO-VID: 6267d97e-7d02-4695-9b46-eb2604e8709d

License:

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 5 March 2023

Date revision received : 6 August 2023

Date accepted : 15 August 2023

Funding

Funded by: FundRef https://doi.org/10.13039/501100001809, National Natural Science Foundation of China (National Science Foundation of China);

Award ID: 82072675, 82273197,

Award ID: 82073856

Award ID: 82173820

Award Recipient : Wenjie Guo Wen Liu Yanhong Gu

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ScienceOpen disciplines: Cell biology

Keywords: targeted therapies,pattern recognition receptors

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ScienceOpen disciplines: Cell biology

Keywords: targeted therapies, pattern recognition receptors

A HER2-targeting antibody-MMAE conjugate RC48 sensitizes immunotherapy in HER2-positive colon cancer by triggering the cGAS-STING pathway

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Cancer Immunotherapy

Most cited references 33

Cancer statistics in China and United States, 2022: profiles, trends, and determinants

ESMO consensus guidelines for the management of patients with metastatic colorectal cancer.

Immunotherapy in colorectal cancer: rationale, challenges and potential

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