A Novel Role for the Interleukin-1 Receptor Axis in Resistance to Anti-EGFR Therapy
Cetuximab (CTX) is a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), commonly used to treat patients with metastatic colorectal cancer (mCRC). Unfortunately, objective remissions occur only in a minority of patients and are of short duration, with a population of cells sur...
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| Format: | Article |
| Language: | English |
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MDPI AG
2018-09-01
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| Series: | Cancers |
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| Online Access: | http://www.mdpi.com/2072-6694/10/10/355 |
| _version_ | 1797764716907462656 |
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| author | Valerio Gelfo Martina Mazzeschi Giada Grilli Moshit Lindzen Spartaco Santi Gabriele D’Uva Balázs Győrffy Andrea Ardizzoni Yosef Yarden Mattia Lauriola |
| author_facet | Valerio Gelfo Martina Mazzeschi Giada Grilli Moshit Lindzen Spartaco Santi Gabriele D’Uva Balázs Győrffy Andrea Ardizzoni Yosef Yarden Mattia Lauriola |
| author_sort | Valerio Gelfo |
| collection | DOAJ |
| description | Cetuximab (CTX) is a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), commonly used to treat patients with metastatic colorectal cancer (mCRC). Unfortunately, objective remissions occur only in a minority of patients and are of short duration, with a population of cells surviving the treatment and eventually enabling CTX resistance. Our previous study on CRC xenopatients associated poor response to CTX with increased abundance of a set of pro-inflammatory cytokines, including the interleukins IL-1A, IL-1B and IL-8. Stemming from these observations, our current work aimed to assess the role of IL-1 pathway activity in CTX resistance. We employed a recombinant decoy TRAP IL-1, a soluble protein combining the human immunoglobulin Fc portion linked to the extracellular region of the IL-1-receptor (IL-1R1), able to sequester IL-1 directly from the medium. We generated stable clones expressing and secreting a functional TRAP IL-1 into the culture medium. Our results show that IL-1R1 inhibition leads to a decreased cell proliferation and a dampened MAPK and AKT axes. Moreover, CRC patients not responding to CTX blockage displayed higher levels of IL-1R1 than responsive subjects, and abundant IL-1R1 is predictive of survival in patient datasets specifically for the consensus molecular subtype 1 (CMS1). We conclude that IL-1R1 abundance may represent a therapeutic marker for patients who become refractory to monoclonal antibody therapy, while inhibition of IL-1R1 by TRAP IL-1 may offer a novel therapeutic strategy. |
| first_indexed | 2024-03-12T19:59:45Z |
| format | Article |
| id | doaj.art-4e5803f27c6b4d12855f83e0ff3de709 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T19:59:45Z |
| publishDate | 2018-09-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-4e5803f27c6b4d12855f83e0ff3de7092023-08-02T02:29:24ZengMDPI AGCancers2072-66942018-09-01101035510.3390/cancers10100355cancers10100355A Novel Role for the Interleukin-1 Receptor Axis in Resistance to Anti-EGFR TherapyValerio Gelfo0Martina Mazzeschi1Giada Grilli2Moshit Lindzen3Spartaco Santi4Gabriele D’Uva5Balázs Győrffy6Andrea Ardizzoni7Yosef Yarden8Mattia Lauriola9Department of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138 Bologna, ItalyDepartment of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138 Bologna, ItalyDepartment of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138 Bologna, ItalyDepartment of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, IsraelInstitute of Molecular Genetics, National Research Council of Italy, 40136 Bologna, ItalyScientific and Technology Pole, IRCCS MultiMedica, 20138 Milan, ItalyMTA TTK Lendület Cancer Biomarker Research Group, Institute of Enzymology, Magyar Tudósok körútja 2, 1117 Budapest, HungaryDepartment of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138 Bologna, ItalyDepartment of Biological Regulation, Weizmann Institute of Science, 7610001 Rehovot, IsraelDepartment of Experimental, Diagnostic and Specialty Medicine (DIMES), University of Bologna, 40138 Bologna, ItalyCetuximab (CTX) is a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), commonly used to treat patients with metastatic colorectal cancer (mCRC). Unfortunately, objective remissions occur only in a minority of patients and are of short duration, with a population of cells surviving the treatment and eventually enabling CTX resistance. Our previous study on CRC xenopatients associated poor response to CTX with increased abundance of a set of pro-inflammatory cytokines, including the interleukins IL-1A, IL-1B and IL-8. Stemming from these observations, our current work aimed to assess the role of IL-1 pathway activity in CTX resistance. We employed a recombinant decoy TRAP IL-1, a soluble protein combining the human immunoglobulin Fc portion linked to the extracellular region of the IL-1-receptor (IL-1R1), able to sequester IL-1 directly from the medium. We generated stable clones expressing and secreting a functional TRAP IL-1 into the culture medium. Our results show that IL-1R1 inhibition leads to a decreased cell proliferation and a dampened MAPK and AKT axes. Moreover, CRC patients not responding to CTX blockage displayed higher levels of IL-1R1 than responsive subjects, and abundant IL-1R1 is predictive of survival in patient datasets specifically for the consensus molecular subtype 1 (CMS1). We conclude that IL-1R1 abundance may represent a therapeutic marker for patients who become refractory to monoclonal antibody therapy, while inhibition of IL-1R1 by TRAP IL-1 may offer a novel therapeutic strategy.http://www.mdpi.com/2072-6694/10/10/355cetuximabcolon cancerinflammationcolonspheresMAPKconsensus molecular subtyperesistance |
| spellingShingle | Valerio Gelfo Martina Mazzeschi Giada Grilli Moshit Lindzen Spartaco Santi Gabriele D’Uva Balázs Győrffy Andrea Ardizzoni Yosef Yarden Mattia Lauriola A Novel Role for the Interleukin-1 Receptor Axis in Resistance to Anti-EGFR Therapy Cancers cetuximab colon cancer inflammation colonspheres MAPK consensus molecular subtype resistance |
| title | A Novel Role for the Interleukin-1 Receptor Axis in Resistance to Anti-EGFR Therapy |
| title_full | A Novel Role for the Interleukin-1 Receptor Axis in Resistance to Anti-EGFR Therapy |
| title_fullStr | A Novel Role for the Interleukin-1 Receptor Axis in Resistance to Anti-EGFR Therapy |
| title_full_unstemmed | A Novel Role for the Interleukin-1 Receptor Axis in Resistance to Anti-EGFR Therapy |
| title_short | A Novel Role for the Interleukin-1 Receptor Axis in Resistance to Anti-EGFR Therapy |
| title_sort | novel role for the interleukin 1 receptor axis in resistance to anti egfr therapy |
| topic | cetuximab colon cancer inflammation colonspheres MAPK consensus molecular subtype resistance |
| url | http://www.mdpi.com/2072-6694/10/10/355 |
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