Tocilizumab overcomes chemotherapy resistance in mesenchymal stem-like breast cancer by negating autocrine IL-1A induction of IL-6

Chung, Andrew W.; Kozielski, Anthony J.; Qian, Wei; Zhou, Jianying; Anselme, Ann C.; Chan, Alfred A.; Pan, Ping-Ying; Lee, Delphine J.; Chang‐Claude, Jenny

doi:10.1038/s41523-021-00371-0

Cited by 17 publications

(11 citation statements)

References 59 publications

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“…Cytokines and growth factors secreted in cancer cells can lead to persistent activation of STAT3 and, consequently, to tumorigenesis. Among cytokines, based on its association with drug resistance, IL-6 could be a relevant therapeutic target [ 50 , 51 ].…”

Section: Discussionmentioning

confidence: 99%

Role of IL-6/STAT3 Axis in Resistance to Cisplatin in Gastric Cancers

et al. 2023

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Gastric cancer, the second most common cause of death worldwide, is characterized by poor prognosis and low responsiveness to chemotherapy. Indeed, multidrug resistance, based mainly on cellular and molecular factors, remains one of the most limiting factors of the current approach to gastric cancer (GC) therapy. We employed a comprehensive gene expression analysis through data mining of publicly available databases to assess the role of the signal transducer and activator of transcription 3 (STAT3) in gastric cancer drug efficiency. It has been proposed that gastric cancer cells are less sensitive to these drugs because they develop resistance to these agents through activating alternative signalling pathways responsible for overcoming pharmacological inhibition. Our study evaluated the hypothesis that activating STAT3 signalling in response to cisplatin reduces the reaction to the drug. Consistent with this hypothesis, inhibition of interleukin 6 (IL-6)/STAT3 in combination therapy with cisplatin prevented both STAT3 activation and more lethality than induction by a single agent. The data suggest that the IL-6/STAT3 axis block associated with cisplatin treatment may represent a strategy to overcome resistance.

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Section: Discussionmentioning

confidence: 99%

Role of IL-6/STAT3 Axis in Resistance to Cisplatin in Gastric Cancers

et al. 2023

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“…Indeed, pre-clinical data demonstrated that IL6 blockade combined with CD40 stimulation sensitized glioblastoma to immune checkpoint inhibitors and improved survival ( 129 , 130 ). Likewise, pre-clinical investigations revealed that targeting of the IL6 signaling might be beneficial for other cancers as well, where bad prognosis is associated with high IL6 level such as renal cell carcinoma ( 131 , 132 ), non-small cell lung cancer ( 133 ), and breast cancer ( 134 ). We found a single, currently suspended clinical trial of the IL6R antibody tocilizumab for gliomas and glioblastoma treatment (NCT04729959), trials for metastatic breast cancer (NCT03135171), non-small lung cancer among others (NCT04940299, Table 4 ).…”

Section: Molecules Involved In the Ctc Heterotypic Interaction And Kn...mentioning

confidence: 99%

Molecules promoting circulating clusters of cancer cells suggest novel therapeutic targets for treatment of metastatic cancers

Rozenberg

Buzdin²,

Mohammad³

et al. 2023

Front. Immunol.

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Treatment of metastatic disease remains among the most challenging tasks in oncology. One of the early events that predicts a poor prognosis and precedes the development of metastasis is the occurrence of clusters of cancer cells in the blood flow. Moreover, the presence of heterogeneous clusters of cancerous and noncancerous cells in the circulation is even more dangerous. Review of pathological mechanisms and biological molecules directly involved in the formation and pathogenesis of the heterotypic circulating tumor cell (CTC) clusters revealed their common properties, which include increased adhesiveness, combined epithelial-mesenchymal phenotype, CTC-white blood cell interaction, and polyploidy. Several molecules involved in the heterotypic CTC interactions and their metastatic properties, including IL6R, CXCR4 and EPCAM, are targets of approved or experimental anticancer drugs. Accordingly, analysis of patient survival data from the published literature and public datasets revealed that the expression of several molecules affecting the formation of CTC clusters predicts patient survival in multiple cancer types. Thus, targeting of molecules involved in CTC heterotypic interactions might be a valuable strategy for the treatment of metastatic cancers.

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“…Based on this finding, a Phase I clinical trial started from 2017 with combined treatment including trastuzumab and tocilizumab for patients with metastatic trastuzumab-resistant HER2+ breast cancer was carried out (NCT03135171). According to the reported literature, IL-6 signaling is a major determinant of TNBC cell proliferation and viability ( 123 ), and this chemotherapy-associated inflammatory cytokine may promote resistance mechanisms in TNBC cells as well ( 124 ). A Phase Ib/II, open-label, multicenter, randomized umbrella study is being carried out to evaluate the efficacy and safety of multiple immunotherapy-based treatment combinations including tocilizumab in patients with metastatic or inoperable locally advanced TNBC (NCT03424005).…”

Section: Il-6’s Functional Role In Breast Cancer Developmentmentioning

confidence: 99%

IL-6: The Link Between Inflammation, Immunity and Breast Cancer

et al. 2022

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Breast cancer is one of the leading causes of mortality in females. Over the past decades, intensive efforts have been made to uncover the pathogenesis of breast cancer. Interleukin-6 (IL-6) is a pleiotropic factor which has a vital role in host defense immunity and acute stress. Moreover, a wide range of studies have identified the physiological and pathological roles of IL-6 in inflammation, immune and cancer. Recently, several IL-6 signaling pathway-targeted monoclonal antibodies have been developed for cancer and immune therapy. Combination of IL-6 inhibitory antibody with other pathways blockage drugs have demonstrated promising outcome in both preclinical and clinical trials. This review focuses on emerging studies on the strong linkages of IL-6/IL-6R mediated regulation of inflammation and immunity in cancer, especially in breast cancer.

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Tocilizumab overcomes chemotherapy resistance in mesenchymal stem-like breast cancer by negating autocrine IL-1A induction of IL-6

Cited by 17 publications

References 59 publications

Role of IL-6/STAT3 Axis in Resistance to Cisplatin in Gastric Cancers

Role of IL-6/STAT3 Axis in Resistance to Cisplatin in Gastric Cancers

Molecules promoting circulating clusters of cancer cells suggest novel therapeutic targets for treatment of metastatic cancers

IL-6: The Link Between Inflammation, Immunity and Breast Cancer

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