Serum IGF1 Is a Prognostic Marker for Resistance to Targeted Therapies and a Predictive Marker for Anti-IGF1 Receptor Therapy in Melanoma.

Since 2013, the use of combined BRAF (BRAFi) and MEK (MEKi) inhibitors has significantly improved survival in patients with metastatic melanoma. However, melanoma cells are able to evade these treatments, and the five-year survival rates for patients with advanced melanoma is around 30% ( Dummer et al., 2022 Dummer R. Flaherty K.T. Robert C. Arance A. de Groot J.W.B. Garbe C. et al. COLUMBUS 5-Year Update: A Randomized, Open-Label, Phase III Trial of Encorafenib Plus Binimetinib Versus Vemurafenib or Encorafenib in Patients With BRAF V600-Mutant Melanoma. J Clin Oncol. 20 déc. 2022; 40: 4178-4188 Crossref Scopus (26) Google Scholar ). Among the mechanisms of acquired resistance to targeted therapies, the insulin-like growth factor-1 receptor (IGF1R) pathway has been identified as a driver of melanoma progression and BRAFi drug resistance ( Yeh et al., 2006 Yeh A.H. Bohula E.A. Macaulay V.M. Human melanoma cells expressing V600E B-RAF are susceptible to IGF1R targeting by small interfering RNAs. Oncogene. oct. 2006; 25: 6574-6581 Crossref PubMed Scopus (48) Google Scholar ; Villanueva et al., 2010 Villanueva J. Vultur A. Lee J.T. Somasundaram R. Fukunaga-Kalabis M. Cipolla A.K. et al. Acquired Resistance to BRAF Inhibitors Mediated by a RAF Kinase Switch in Melanoma Can Be Overcome by Cotargeting MEK and IGF-1R/PI3K. Cancer Cell. déc. 2010; 18: 683-695 Abstract Full Text Full Text PDF PubMed Scopus (1041) Google Scholar ; Girnita et al., 2014 Girnita L. Worrall C. Takahashi S.I. Seregard S. Girnita A. Something old, something new and something borrowed: emerging paradigm of insulin-like growth factor type 1 receptor (IGF-1R) signaling regulation. Cell Mol Life Sci. 2014; 71: 2403-2427 Crossref PubMed Scopus (121) Google Scholar ; Obenauf et al., 2015 Obenauf A.C. Zou Y. Ji A.L. Vanharanta S. Shu W. Shi H. et al. Therapy-induced tumour secretomes promote resistance and tumour progression. Nature. 16 avr. 2015; 520: 368-372 Crossref PubMed Scopus (350) Google Scholar ; Strub et al. 2018; Patel et al., 2021 Patel H. Mishra R. Yacoub N. Alanazi S. Kilroy M.K. Garrett J.T. IGF1R/IR Mediates Resistance to BRAF and MEK Inhibitors in BRAF-Mutant Melanoma. Cancers. janv. 2021; 13: 5863 Crossref Scopus (11) Google Scholar ; Xu et al., 2022 Xu G. Luo Y. Wu W. Liu X. Yu X. Bao Y. et al. The Evolution of Acquired Resistance to BRAFV600E kinase inhibitor Is Sustained by IGF1-Driven Tumor Vascular Remodeling. J Invest Dermatol. févr. 2022; 142: 445-458 Abstract Full Text Full Text PDF Scopus (8) Google Scholar ). Furthermore, high circulating IGF1 levels have been associated with a higher risk of metastatic melanoma ( Kucera et al., 2014 Kucera R. Treskova I. Vrzalova J. Svobodova S. Topolcan O. Fuchsova R. et al. Evaluation of IGF1 Serum Levels in Malignant Melanoma and Healthy Subjects. Anticancer Res. 9 janv. 2014; 34: 5217-5220 PubMed Google Scholar ), but this was not confirmed in a recent prospective study ( Bradbury et al., 2019 Bradbury K.E. Appleby P.N. Tipper S.J. Travis R.C. Allen N.E. Kvaskoff M. et al. Circulating insulin-like growth factor I in relation to melanoma risk in the European prospective investigation into cancer and nutrition. International Journal of Cancer. 2019; 144: 957-966 Google Scholar ). Therefore, targeting the IGF1/IGF1R pathway emerges as an attractive therapeutic strategy for melanoma patients who escape BRAFi/MEKi therapy. However, several phase II/III clinical trials of drugs targeting this pathway in unselected patients with different solid cancers have shown limited antitumor activity and/or unacceptable adverse effects ( Qu et al., 2017 Qu X. Wu Z. Dong W. Zhang T. Wang L. Pang Z. et al. Update of IGF-1 receptor inhibitor (ganitumab, dalotuzumab, cixutumumab, teprotumumab and figitumumab) effects on cancer therapy. Oncotarget. 25 févr. 2017; 8: 29501-29518 Crossref Scopus (59) Google Scholar ; Truong et al., 2022 Truong D.D. Lamhamedi-Cherradi S.E. Ludwig J.A. Targeting the IGF/PI3K/ mTOR pathway and AXL/YAP1/TAZ pathways in primary bone cancer. J Bone Oncol. 2022; 33100419 Crossref Scopus (3) Google Scholar ), pointing the need to identify patients for whom targeting IGF1/IGF1R would be beneficial.