Single nucleotide polymorphisms in the IGF‐IRS pathway are associated with outcome in mCRC patients enrolled in the FIRE‐3 trial

Abstract

The Insulin-like growth factor (IGF)/IGF-receptor pathway with its scaffolding proteins Insulin Receptor Substrate (IRS)1 and IRS2 are crucial regulators of metabolism and progression in metastatic colorectal cancer (mCRC). The goal of the study was the identification of predictive and prognostic markers among IRS1, IRS2, IGF1 and IGF-1R SNPs in mCRC patients enrolled in the FIRE-3 trial. Four SNPs of IRS (IRS1 rs1801278, rs1801123; IRS2 rs1805097, rs2289046) and 4 SNPs of IGF1-IGFR1 (rs6214, rs6220, rs2946834, rs2016347) were analyzed by PCR/direct-sequencing in the FIRE-3 trial. The relation of SNPs with PFS and OS was evaluated through Kaplan-Meier method and log-rank test in the overall population and in subgroup according to RAS status and treatment arm. In the overall population IRS1 rs1801123 C/- carriers (N= 105) achieved significantly worse OS compared to T/T (N=464) in univariate (HR=1.32 [95%CI 1.03–1.70], p=0.029) and in multivariable. Similar results were observed among RAS wild type. Patients with IGF1 rs2946834 T/- variant (N= 280) achieved improved PFS compared to C/C (N=257) in univariate (HR=0.77 [95%CI 0.64–0.92], p=0.004) and in multivariable. In the RAS wild-type subgroup IGF1 rs2946834 T/- carriers showed better PFS and OS compared to C/C (univariate HR for PFS=0.65 [95%CI 0.51–0.81], p<0.001; multivariable HR for PFS=0.63 [95%CI 0.50–0.81], p<0.001). IRS1 rs1801123 SNP was identified as a new prognostic marker for mCRC. IGF1 rs2946834 was confirmed as prognostic factor in the overall population and in RAS wild type patients. Our findings underline the importance of IGF downstream signaling pathway in RAS wild-type mCRC patient.

IGF1 receptor inhibition amplifies the effects of cancer drugs by autophagy and immune-dependent mechanisms

“…A recent report on patients with colorectal cancer treated with chemotherapy together with EGFR or VEGF inhibitor revealed that overactivation of the IGF1R also constitutes a poor prognostic factor, particularly in patients bearing RAS wild-type tumors. 62 These findings echo prior observations that high expression of IGF1R (though without proof of its activation) is a poor prognostic biomarker in gastric 63 and breast cancer. 1 In conclusion, excessive antiautophagic signaling via IGF1R has a major negative effect on anticancer immunosurveillance, thus reducing patient prognosis.…”

The effects of genetic variants related to insulin metabolism pathways and the interactions with lifestyles on colorectal cancer risk

“…IRS1 is a scaffolding protein that activates and regulates downstream cell-signaling pathways such as PI3K/Akt, leading to metabolic activity, including glucose uptake and protein synthesis, and decreased apoptosis. This pathway is a main signaling cascade in controlling the cellular process promoting carcinogenesis 11,38 . IRS1 and a single member of the Akt family, Akt2, are important signaling molecules related to a diabetic phenotype such as IR; at the genomic level, each is amplified in various cancers, including CRC 11,39,40 .…”

“…This pathway is a main signaling cascade in controlling the cellular process promoting carcinogenesis 11,38 . IRS1 and a single member of the Akt family, Akt2, are important signaling molecules related to a diabetic phenotype such as IR; at the genomic level, each is amplified in various cancers, including CRC 11,39,40 . The IRS1 and AKT2 genes are thus key components of this pathway, but studies of the association of their genetic variants with CRC have been limited and conflicted 11,14,[40][41][42][43][44] .…”

“…IRS1 and a single member of the Akt family, Akt2, are important signaling molecules related to a diabetic phenotype such as IR; at the genomic level, each is amplified in various cancers, including CRC 11,39,40 . The IRS1 and AKT2 genes are thus key components of this pathway, but studies of the association of their genetic variants with CRC have been limited and conflicted 11,14,[40][41][42][43][44] . For example, the IRS1 rs1801278 G (C in our study) allele has higher 43,44 , inverse 41 , or no 11,14 association with CRC risk.…”

“…The overexpression leads to the enhanced anabolic state necessary for cell proliferation, differentiation, and anti-apoptosis, via deregulating or overactivating multiple downstream cellular signaling cascades, including insulin receptor substrate-1 (IRS1) and the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway 9,10 . The IRS1 and PI3K/Akt pathway are overexpressed in CRC patients 11 . Thus, high IGF-I levels and IR, through overexpression of relevant receptors and abnormal multiple cell-signaling pathways, may exert their effects on carcinogenesis.…”