Senescence-associated reprogramming induced by interleukin-1 impairs response to EGFR neutralization
Tóm tắt
EGFR targeting is currently the main treatment strategy for metastatic colorectal cancer (mCRC). Results of different clinical trials show that patients with wild-type KRAS and BRAF benefit from anti-EGFR monoclonal antibodies (moAbs) cetuximab (CTX) or panitumumab. Unfortunately, despite initial response, patients soon became refractory. Tumor heterogeneity and multiple escaping routes have been addressed as the main culprit, and, behind genomic alterations already described, changes in signaling pathways induced by drug pressure are emerging as mechanisms of acquired resistance. We previously reported an association between reduced sensitivity to CTX and increased expression of IL-1. However, how IL-1 mediates CTX resistance in mCRC is still unclear. Under CTX treatment, the upregulation of IL-1R1 expression and a senescence program in sensitive colorectal cancer (CRC) cell lines is examined over time using qPCR, immunoblotting, and immunofluorescence. In sensitive CRC cells, IL-1 appeared responsible for a CTX-mediated G0 phase arrest. On the contrary, CTX-resistant CRC cells (CXR) maintained high mRNA levels of IL-1R1 and a post-senescence reprogramming, as indicated by increased SNAIL expression. Interestingly, treatment of CXR cells with a recombinant decoy, able to sequester the soluble form of IL-1, pushed CTX-resistant CRC cells back into a stage of senescence, thus blocking their proliferation. Our model suggests a trans-regulatory mechanism mediated by IL-1 on EGFR signaling. By establishing senescence and regulating EGFR activity and expression, IL-1 exposure ultimately bestows resistance. To sum up, our findings point to the combined blockage of IL-1R and EGFR as a promising therapeutical approach to restore sensitivity to EGFR-targeting monoclonal antibodies.
Tài liệu tham khảo
Ferlizza E, Solmi R, Sgarzi M, Ricciardiello L, Lauriola M. The roadmap of colorectal cancer screening. Cancers (Basel). 2021;13(5):1101.
Allegra CJ, Rumble RB, Hamilton SR, Mangu PB, Roach N, Hantel A, et al. Extended RAS gene mutation testing in metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy: American Society of Clinical Oncology Provisional Clinical Opinion update 2015. J Clin Oncol. 2016;34(2):179–85.
Sorich MJ, Wiese MD, Rowland A, Kichenadasse G, McKinnon RA, Karapetis CS. Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: a meta-analysis of randomized, controlled trials. Ann Oncol. 2015;26(1):13–21.
Pietrantonio F, Cremolini C, Petrelli F, Di Bartolomeo M, Loupakis F, Maggi C, et al. First-line anti-EGFR monoclonal antibodies in panRAS wild-type metastatic colorectal cancer: a systematic review and meta-analysis. Crit Rev Oncol Hematol. 2015;96(1):156–66.
Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, De Braud F, et al. Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol. 2009;27:663–71.
Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26(10):1626–34.
Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, et al. Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008;26:5705–12.
Karapetis CS, Khambata-Ford S, Jonker DJ, O’Callaghan CJ, Tu D, Tebbutt NC, et al. K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 2008;359:1757–65.
Bray SM, Lee J, Kim ST, Hur JY, Ebert PJ, Calley JN, et al. Genomic characterization of intrinsic and acquired resistance to cetuximab in colorectal cancer patients. Sci Rep. 2019;9(1):15365.
Misale S, Di Nicolantonio F, Sartore-Bianchi A, Siena S, Bardelli A. Resistance to anti-EGFR therapy in colorectal cancer: from heterogeneity to convergent evolution. Cancer Discov. 2014;4:1269–80.
Dienstmann R, Salazar R, Tabernero J. Overcoming resistance to anti-EGFR therapy in colorectal cancer. Am Soc Clin Oncol Educ B. 2015. https://doi.org/10.14694/EdBook_AM.2015.35.e149.
Gelfo V, Rodia MT, Pucci M, Dall’Ora M, Santi S, Solmi R, et al. A module of inflammatory cytokines defines resistance of colorectal cancer to EGFR inhibitors. Oncotarget. 2016;7(44):72167–83.
Gelfo V, Mazzeschi M, Grilli G, Lindzen M, Santi S, D’Uva G, et al. A novel role for the Interleukin-1 receptor axis in resistance to anti-EGFR therapy. Cancers (Basel). 2018;10:335.
Hernandez-Segura A, Nehme J, Demaria M. Hallmarks of cellular senescence. Trends Cell Biol. 2018;28(6):436–53.
Wyld L, Bellantuono I, Tchkonia T, Morgan J, Turner O, Foss F, et al. Senescence and cancer: a review of clinical implications of senescence and senotherapies. Cancers (Basel). 2020;12(8):2134.
Lee S, Schmitt CA. The dynamic nature of senescence in cancer. Nat Cell Biol. 2019;21(1):94–101.
Saleh T, Tyutyunyk-Massey L, Murray GF, Alotaibi MR, Kawale AS, Elsayed Z, et al. Tumor cell escape from therapy-induced senescence. Biochem Pharmacol. 2019;162:202–12.
Konner J, Dupont J. Use of soluble recombinant decoy receptor vascular endothelial growth factor trap (VEGF Trap) to inhibit vascular endothelial growth factor activity. Clin Colorectal Cancer. 2004;4(Suppl 2):81–5.
Lindzen M, Carvalho S, Starr A, Ben-Chetrit N, Pradeep CR, Köstler WJ, et al. A recombinant decoy comprising EGFR and ErbB-4 inhibits tumor growth and metastasis. Oncogene. 2012;31:3505–15.
Coppé J-P, Desprez P-Y, Krtolica A, Campisi J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu Rev Pathol Mech Dis. 2010;5(1):99–118.
Sun Y, Coppé JP, Lam EWF. Cellular senescence: the sought or the unwanted? Trends Mol Med. 2018;24:871–85.
Bojko A, Czarnecka-Herok J, Charzynska A, Dabrowski M, Sikora E. Diversity of the senescence phenotype of cancer cells treated with chemotherapeutic agents. Cells. 2019;8(12):1501.
González-Gualda E, Baker AG, Fruk L, Muñoz-Espín D. A guide to assessing cellular senescence in vitro and in vivo. FEBS J. 2021;288(1):56–80.
Jochems F, Thijssen B, De Conti G, Jansen R, Pogacar Z, Groot K, et al. The cancer SENESCopedia: a delineation of cancer cell senescence. Cell Rep. 2021. https://doi.org/10.2139/ssrn.3762763.
Cho S, Park J, Hwang ES. Kinetics of the cell biological changes occurring in the progression of DNA damage-induced senescence. Mol Cells. 2011;31(6):539–46.
Marrocco I, Romaniello D, Yarden Y. Cancer immunotherapy: the dawn of antibody cocktails. Methods Mol Biol. 2019;1904:11–51.
Ferraro DA, Gaborit N, Maron R, Cohen-Dvashi H, Porat Z, Pareja F, et al. Inhibition of triple-negative breast cancer models by combinations of antibodies to EGFR. Proc Natl Acad Sci USA. 2013;110(5):1815–20.
Cano A, Pérez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol. 2000;2(2):76–83.
Zhang R, Chen W, Adams PD. Molecular dissection of formation of senescence-associated heterochromatin foci. Mol Cell Biol. 2007;27(6):2343–58.
Russo M, Crisafulli G, Sogari A, Reilly NM, Arena S, Lamba S, et al. Adaptive mutability of colorectal cancers in response to targeted therapies. Science. 2019;366:1473–80.
Collin G, Huna A, Warnier M, Flaman JM, Bernard D. Transcriptional repression of DNA repair genes is a hallmark and a cause of cellular senescence article. Cell Death Dis. 2018. https://doi.org/10.1038/s41419-018-0300-z.
Gelfo V, Romaniello D, Mazzeschi M, Sgarzi M, Grilli G, Morselli A, et al. Roles of il-1 in cancer: from tumor progression to resistance to targeted therapies. Int J Mol Sci. 2020;21:1–14.
Obenauf AC, Zou Y, Ji AL, Vanharanta S, Shu W, Shi H, et al. Therapy-induced tumour secretomes promote resistance and tumour progression. Nature. 2015;520:368–72.
Uruski P, Sepetowska A, Konieczna C, Pakuła M, Wyrwa M, Tussupkaliyev A, et al. Primary high-grade serous ovarian cancer cells are sensitive to senescence induced by carboplatin and paclitaxel in vitro. Cell Mol Biol Lett. 2021. https://doi.org/10.1186/s11658-021-00287-4.
Herranz N, Gil J. Mechanisms and functions of cellular senescence. J Clin Invest. 2018;128(4):1238–46.
Vernot JP. Senescence-associated pro-inflammatory cytokines and tumor cell plasticity. Front Mol Biosci. 2020;7:63.
Milanovic M, Fan DNYY, Belenki D, Däbritz JHM, Zhao Z, Yu Y, et al. Senescence-associated reprogramming promotes cancer stemness. Nature. 2018;553:96–100.
Nekulova M, Holcakova J, Coates P, Vojtesek B. The role of P63 in cancer, stem cells and cancer stem cells. Cell Mol Biol Lett. 2011. https://doi.org/10.2478/s11658-011-0009-.
Saleh T, Carpenter VJ. Potential use of senolytics for pharmacological targeting of precancerous lesions. Mol Pharmacol. 2021;100:580–7.
Ridker PM, MacFadyen JG, Thuren T, Everett BM, Libby P, Glynn RJ, et al. Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomised, double-blind, placebo-controlled trial. Lancet. 2017;390(10105):1833–42.
Wang L, Leite de Oliveira R, Wang C, Fernandes Neto JM, Mainardi S, Evers B, et al. High-throughput functional genetic and compound screens identify targets for senescence induction in cancer. Cell Rep. 2017;21:773–83.