Germline Polymorphisms in Genes Involved in the IGF1 Pathway Predict Efficacy of Cetuximab in Wild-type KRAS mCRC Patients
Open accessAbstract
Purpose: The insulin-like growth factor 1 (IGF1) signaling pathway is an important growth-regulatory pathway, which plays a crucial role in colorectal cancer (CRC) proliferation, differentiation, migration, angiogenesis, and apoptosis. Previous studies showed that hyperactivation of the IGF1 receptor (IGF1R) may result in resistance to anti–epidermal growth factor receptor–targeted treatment. We tested whether germline variations within the IGF1 pathway are associated with clinical outcome in wild-type (wt) KRAS drug-refractory metastatic CRC (mCRC) patients who were treated with cetuximab monotherapy (IMC-0144). Experimental Design: Formalin-fixed, paraffin-embedded (FFPE) tissue samples of 130 drug-refractory mCRC patients enrolled in IMC-0144, a phase II clinical trial of cetuximab monotherapy, were analyzed. gDNA was extracted from dissected FFPE tumor tissue, and KRAS mutation status and six potentially functional IGF1 and IGF1R polymorphisms were analyzed using direct DNA sequencing or PCR-RFLP. Tumor response analysis was based on recursive partitioning, and survival analyses were based on univariate and multivariate hazard regression models. Results: In univariate and multivariate analyses, five IGF pathway single-nucleotide polymorphisms were significantly associated with progression-free survival (PFS) and/or overall survival (OS). In multivariate combined risk allele analysis, the additive model for PFS and OS was significantly associated with the number of risk alleles in wt KRAS patients (P = 0.001 and P = 0.02, respectively). In addition, wt KRAS patients harboring IGF1 rs2946834 A/A genotype had a 50% objective response rate compared with 0% for A/G genotype. Conclusions: These results indicate that IGF1 pathway polymorphisms are potential predictive/prognostic molecular markers for cetuximab efficacy in wt KRAS mCRC patients. Prospective biomarker-embedded clinical trials are warranted to validate our findings. Clin Cancer Res; 16(22); 5591–602. ©2010 AACR.
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Hyperactivation of IGF-1R results in primary and secondary resistance to EGFR inhibition in RAS wild-type metastatic colorectal cancer by upregulating the PI3K/AKT pathway.
“Hyperactivation of IGF-1R results in primary and secondary resistance to EGFR inhibition in RAS wild-type mCRC by upregulating the PI3K/AKT pathway [117, 118].”
From Resistance to anti-EGFR therapies in metastatic colorectal cancer: underlying mechanisms and reversal strategies (2021) · cites this paper as [117]
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- Authors
- Winder, T., Zhang, W., Yang, D., Ning, Y., Bohanes, P., Gerger, A., Wilson, P. M., Pohl, A., Mauro, D. J., Langer, C., Rowinsky, E. K., & Lenz, H.-J.
- Affiliations
- University of Southern California (US)
- Corresponding author
- Lenz, Heinz-Josef
- Venue
- Clinical Cancer Research
- Published
- 2010-11-14
- Volume
- 16
- Issue
- 22
- Pages
- 5591-5602
- ISSN
- 1078-0432 (ISSN-L)
- 1557-3265
- PMC
- PMC2982939
- OpenAlex
- W2088636164
- Cited by
- 46
- References
- 43
- Citations by year
- 2024: 3 · 2023: 3 · 2022: 1 · 2021: 2 · 2020: 3 · 2019: 1 · 2018: 1 · 2017: 2 · 2016: 7 · 2015: 5 · 2014: 6 · 2013: 4 · 2012: 6
- FWCI
- 1.90
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Clinical Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Cancer Institute (K24CA082754, 5 P30CA14089-27I, P30CA014089)
- Topics
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Growth Hormone and Insulin-like Growth Factors
- Keywords
- cetuximab, IGF-1 receptor, KRAS wild-type, metastatic colorectal cancer, predictive biomarkers, progression-free survival, overall survival, anti-EGFR therapy resistance
- MeSH terms
- Cetuximab, Aged, Antibodies, Monoclonal, Antineoplastic Agents, Genetic Testing, Humans, Insulin-Like Growth Factor I, Middle Aged, Proto-Oncogene Proteins, Colorectal Neoplasms, Signal Transduction, Multivariate Analysis, Proto-Oncogene Proteins p21(ras), Germ-Line Mutation, ras Proteins, Polymorphism, Single Nucleotide, Antibodies, Monoclonal, Humanized
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