Identification of IGF1R mutation as a novel predictor of efficacious immunotherapy in melanoma

Ma, Dongshen; Zhang, Qin; Tan, Yuan; Sun, Tingting; Qi, Chuang; Qin, Yong; Liu, Hui

doi:10.1186/s12967-022-03324-8

Cited by 5 publications

(4 citation statements)

References 3 publications

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“…Indeed, the factors that influence ICI efficacy are extremely diverse and complex. Besides the widely recognized TMB, an increasing number of studies have demonstrated that gene mutations exert considerable impacts on the efficacy of ICIs, with some mutations favoring ICIs and some attenuating ICIs ( 14 , 16 , 25 , 26 ). Notably, FGFR family driver genes are frequently mutated in melanoma, whereas its influence on ICIs efficacy in melanoma remains unknown.…”

Section: Discussionmentioning

confidence: 99%

“…For example, PTPRT mutant melanoma was more responsive to ICIs ( 15 ). In addition, mutations in IGF1R ( 16 ), MAP2K1/2 ( 17 ), ARID1A ( 18 ) and NOTCH4 ( 19 ) were associated with more benefit from ICIs in melanoma, with the tumor immune microenvironment (TIME) modulation and immunogenicity alteration as their potential mechanisms. Hence, it is worthwhile to identify novel key genetic mutations affecting the efficacy of ICIs and explore their potential mechanisms, thereby maximizing the therapeutic benefit of ICIs and reducing immune-related toxicities for patients with melanoma.…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, ICIs are important candidates for FGFR-mutated melanoma. What is to be noted is that studies have proved that genetic mutations can affect the efficacy of ICIs, with some mutations (IGF1R, NOTCH4 and ARID1A) favoring ICIs ( 16 , 18 , 19 ) whereas others (EGFR and ALK) ( 25 , 26 ) weakening their efficacy. In terms of FGFR mutations, a recent study found that FGFR-altered and wild-type bladder cancers had equivalent response rates to ICIs ( 27 ).…”

Section: Introductionmentioning

confidence: 99%

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Fibroblast growth factor receptor family mutations as a predictive biomarker for immune checkpoint inhibitors and its correlation with tumor immune microenvironment in melanoma

Zhang

Xia²,

Yang³

et al. 2022

Front. Immunol.

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BackgroundThe emergence of immune checkpoint inhibitors (ICIs) has significantly improved the clinical outcomes of patients with metastatic melanoma. However, survival benefits are only observed in a subset of patients. The fibroblast growth factor receptor (FGFR) family genes are frequently mutated in melanoma, yet their impacts on the efficacy of ICIs remain unclear. Our study aimed to explore the association of FGFR mutations with ICIs efficacy in metastatic melanoma.MethodsThe Cancer Genome Atlas (TCGA) data (PanCancer Atlas, skin cutaneous melanoma (SKCM), n = 448) in cBioPortal were collected as a TCGA cohort to investigate the association between FGFR mutations and prognosis of melanoma patients. To explore the impact of FGFR mutations on the efficacy of ICIs in melanoma, clinical and tumor whole-exome sequencing (WES) data of four ICI-treated studies from cBioPortal were consolidated as an ICIs-treated cohort. Moreover, the relationship between FGFR mutations and immunogenicity (tumor mutation burden (TMB), neo-antigen load (NAL), mismatch repair (MMR)-related genes and DNA damage repair (DDR)-related genes) of melanoma was evaluated utilizing data from the ICIs-treated cohort. The influence of FGFR mutations on the tumor immune microenvironment (TIME) of melanoma was also analyzed using the TCGA cohort.ResultsIn the TCGA cohort, survival in melanoma patients with or without FGFR mutations was nearly equivalent. In the ICIs-treated cohort, patients with FGFR mutations had better survival than those without (median overall survival: 60.00 vs. 31.00 months; hazard ratio: 0.58, 95% CI: 0.42-0.80; P = 0.0051). Besides, the objective response rate was higher for patients harboring FGFR mutations (55.56%) compared to wild-type patients (22.40%) (P = 0.0076). Mechanistically, it was revealed that FGFR mutations correlated with increased immunogenicity (e.g., TMB, NAL, MMR-related gene mutations and DDR-related gene mutations). Meanwhile, FGFR mutant melanoma tended to exhibit an enhanced antitumor TIME compared with its wild-type counterparts.ConclusionsOur study demonstrated that FGFR mutations is a promising biomarker in stratifying patients with advanced melanoma who might benefit from ICIs therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Fibroblast growth factor receptor family mutations as a predictive biomarker for immune checkpoint inhibitors and its correlation with tumor immune microenvironment in melanoma

Zhang

Xia²,

Yang³

et al. 2022

Front. Immunol.

View full text Add to dashboard Cite

show abstract

“…However, such a multiplicity of effects is not exclusively due to the action of canonical components of this axis but is rather due to a complex network of regulators and interactors, which potentiate or antagonize IGF expression and/or function. In cancer, mutations in the IGF genes are relatively uncommon, with very few exceptions [ 6 , 7 ]. More frequently, transcriptional, post-transcriptional or functional alterations induce unbalanced IGF activity in tumor cells more than genetic ones [ 8 , 9 ].…”

Section: Introductionmentioning

confidence: 99%

Extracellular Interactors of the IGF System: Impact on Cancer Hallmarks and Therapeutic Approaches

Mancarella,

Morrione,

Scotlandi

2024

IJMS

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Dysregulation of the insulin-like growth factor (IGF) system determines the onset of various pathological conditions, including cancer. Accordingly, therapeutic strategies have been developed to block this system in tumor cells, but the results of clinical trials have been disappointing. After decades of research in the field, it is safe to say that one of the major reasons underlying the poor efficacy of anti-IGF-targeting agents is derived from an underestimation of the molecular complexity of this axis. Genetic, transcriptional, post-transcriptional and functional interactors interfere with the activity of canonical components of this axis, supporting the need for combinatorial approaches to effectively block this system. In addition, cancer cells interface with a multiplicity of factors from the extracellular compartment, which strongly affect cell destiny. In this review, we will cover novel extracellular mechanisms contributing to IGF system dysregulation and the implications of such dangerous liaisons for cancer hallmarks and responses to known and new anti-IGF drugs. A deeper understanding of both the intracellular and extracellular microenvironments might provide new impetus to better decipher the complexity of the IGF axis in cancer and provide new clues for designing novel therapeutic approaches.

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Immunogenic cell death signatures from on-treatment tumor specimens predict immune checkpoint therapy response in metastatic melanoma

Zeng,

Jiang,

Zhang

et al. 2024

Sci Rep

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Melanoma is a highly malignant form of skin cancer that typically originates from abnormal melanocytes. Despite significant advances in treating metastatic melanoma with immune checkpoint blockade (ICB) therapy, a substantial number of patients do not respond to this treatment and face risks of recurrence and metastasis. This study collected data from multiple datasets, including cohorts from Riaz et al., Gide et al., MGH, and Abril-Rodriguez et al., focusing on on-treatment samples during ICB therapy. We used the single-sample gene set enrichment analysis (ssGSEA) method to calculate immunogenic cell death scores (ICDS) and employed an elastic network algorithm to construct a model predicting ICB efficacy. By analyzing 18 ICD gene signatures, we identified 9 key ICD gene signatures that effectively predict ICB treatment response for on-treatment metastatic melanoma specimens. Results showed that patients with high ICD scores had significantly higher response rates to ICB therapy compared to those with low ICD scores. ROC analysis demonstrated that the AUC values for both the training and validation sets were around 0.8, indicating good predictive performance. Additionally, survival analysis revealed that patients with high ICD scores had longer progression-free survival (PFS). This study used an elastic network algorithm to identify 9 ICD gene signatures related to the immune response in metastatic melanoma. These gene features can not only predict the efficacy of ICB therapy but also provide references for clinical decision-making. The results indicate that ICD plays an important role in metastatic melanoma immunotherapy and that expressing ICD signatures can more accurately predict ICB treatment response and prognosis for on-treatment metastatic melanoma specimens, thus providing a basis for personalized treatment. Supplementary Information The online version contains supplementary material available at 10.1038/s41598-024-74636-6.

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Identification of IGF1R mutation as a novel predictor of efficacious immunotherapy in melanoma

Cited by 5 publications

References 3 publications

Fibroblast growth factor receptor family mutations as a predictive biomarker for immune checkpoint inhibitors and its correlation with tumor immune microenvironment in melanoma

Fibroblast growth factor receptor family mutations as a predictive biomarker for immune checkpoint inhibitors and its correlation with tumor immune microenvironment in melanoma

Extracellular Interactors of the IGF System: Impact on Cancer Hallmarks and Therapeutic Approaches

Immunogenic cell death signatures from on-treatment tumor specimens predict immune checkpoint therapy response in metastatic melanoma

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