Correlation between Gene Expression of IGF-1R Pathway Markers and Cetuximab Benefit in Metastatic Colorectal Cancer

Abstract

Purpose: This study examined potential correlations between markers related to the insulin-like growth factor-1 receptor (IGF-1R) pathway and clinical benefit from the anti-epidermal growth factor receptor (EGFR) monoclonal antibody cetuximab in metastatic colorectal cancer (mCRC).Experimental Design: Gene expression profiles for 70 pretreatment specimens from metastatic lesions of patients with chemorefractory mCRC receiving cetuximab monotherapy were analyzed using 74 predefined Gene-Chip probesets representing 33 unique IGF-1R pathway markers to determine correlations with progression-free survival (PFS) and disease control rate.Results: Higher IGF-1R, higher GRB 7 , and lower INSIG 2 expression were associated with longer PFS with cetuximab in univariate analyses, particularly in patients with wild-type K-Ras tumors: median, 122 versus 60 days (P ¼ 0.01), 122 versus 57 days (P ¼ 0.011), and 57 versus 156 days (P < 0.0001), favoring higher IGF-1R, higher GRB 7 , and lower INSIG 2 expression, respectively. Lower IGF-1 expression was associated with a PFS benefit with cetuximab, whereas lower IGFBP 3 and INSR expression levels showed trends for a PFS benefit. Lower INSIG 2 expression (vs. higher expression) was associated with greater PFS in the high epiregulin-expressing group (P ¼ 0.001), but not in the low-expressing cohort suggesting an effect independent from the previously reported effect of epiregulin expression. Lower INSIG 2 expression was also associated with higher disease control rate in the overall population (51.4% vs. 11.4%; P ¼ 0.001) and wild-type K-Ras subset (76.2% vs. 18.2%; P < 0.0001).Conclusions: These results suggest that markers of the IGF-1R pathway may play a role in predicting benefit from cetuximab therapy in mCRC. Additional clinical studies are warranted to validate these findings.

Contrasted Outcomes to Gefitinib on Tumoral IGF1R Expression in Head and Neck Cancer Patients Receiving Postoperative Chemoradiation (GORTEC Trial 2004-02)

“…Such a result could be explained by off-target, either or indirect, drug effects (38), affecting IGF1R (39), despite the absence of published data. In line with prior reports, Huang and colleagues showed that high IGF1R expression has prognostic value in patients with Kras wild-type colorectal cancers treated with cetuximab (40).…”

“…In cells expressing high levels of RAF dimers, binding of vemurafenib to one member of RAF dimer transactivates non-drug-bound ATP-bound RAF, leading to ERK activation, cell proliferation, and cutaneous squamous cell carcinomas (45). Deleterious effects of EGFR inhibitor cetuximab were previously reported in colorectal studies as a result of KRAS mutations (40,(46)(47)(48)(49). Interestingly, Winder and colleagues showed that wild-type KRAS patients with germline polymorphisms in the IGF1 pathway treated with cetuximab had a significant increase in their risk for tumor progression (50).…”

Expression of insulin-like growth factor receptor type 1 correlate with lymphatic metastases in human gastric cancer

“…Overexpression of IGF-1R has been reported in many human cancers [11][12][13][14][15]. In the literature it has been shown that this receptor plays an important role in cancer cell transformation, tumor cell survival and development [6,20,21].…”

“…It has been shown that IGF-1R activates the mitotic divisions and inhibit apoptosis of cancer cells through the activation of signaling MAP/ERK and PI3K/Akt-1 pathways [6,10]. Overexpression of IGF-1R has been observed in many cancers, including esophageal cancer [11], breast cancer [12], colorectal cancer [13,14] and lung cancer [15]. Due to the important contribution of this receptor to the process of carcinogenesis and metastasis, research on using IGF-1R as a therapeutic target in oncology is being conducted [16].…”

Orally efficacious novel small molecule 6-chloro-6-deoxy-1,2,3,4-tetra-O-galloyl-α-d-glucopyranose selectively and potently stimulates insulin receptor and alleviates diabetes

“…Both IR and IGF1R signaling pathways consist of two major branches, the PI3K-Akt pathway and the MAPK pathway. Any IR signaling activator also tends to activate oncogenic IGF1R signaling (Higashi et al 2010, Lewis et al 2010, Wu et al 2011, Huang et al 2012, Ma et al 2012. Few agents are known to selectively activate IR signaling without triggering IGF1R signaling.…”