» Articles » PMID: 28199979

ATM Mutations and E-cadherin Expression Define Sensitivity to EGFR-targeted Therapy in Colorectal Cancer

Overview
Journal Oncotarget
Specialty Oncology
Date 2017 Feb 16
PMID 28199979
Citations 15
Authors
Affiliations
Soon will be listed here.
Abstract

EGFR-targeted therapy is a key treatment approach in patients with RAS wildtype metastatic colorectal cancers (CRC). Still, also RAS wildtype CRC may be resistant to EGFR-targeted therapy, with few predictive markers available for improved stratification of patients. Here, we investigated response of 7 CRC cell lines (Caco-2, DLD1, HCT116, HT29, LS174T, RKO, SW480) to Cetuximab and correlated this to NGS-based mutation profiles, EGFR promoter methylation and EGFR expression status as well as to E-cadherin expression. Moreover, tissue specimens of primary and/or recurrent tumors as well as liver and/or lung metastases of 25 CRC patients having received Cetuximab and/or Panitumumab were examined for the same molecular markers. In vitro and in situ analyses showed that EGFR promoter methylation and EGFR expression as well as the MSI and or CIMP-type status did not guide treatment responses. In fact, EGFR-targeted treatment responses were also observed in RAS exon 2 p.G13 mutated CRC cell lines or CRC cases and were further linked to PIK3CA exon 9 mutations. In contrast, non-response to EGFR-targeted treatment was associated with ATM mutations and low E-cadherin expression. Moreover, down-regulation of E-cadherin by siRNA in otherwise Cetuximab responding E-cadherin positive cells abrogated their response. Hence, we here identify ATM and E-cadherin expression as potential novel supportive predictive markers for EGFR-targeted therapy.

Citing Articles

Genetic profiling of osteosarcoma in an adolescent using a next‑generation sequencing panel and Sanger sequencing: A case report and review of the literature.

Chantre-Justino M, Silvestre R, De Castro T, Luz E, Pinheiro R, Caruso A Biomed Rep. 2025; 22(3):42.

PMID: 39810900 PMC: 11729137. DOI: 10.3892/br.2025.1920.


Role of Cell-Cell Junctions in Oesophageal Squamous Cell Carcinoma.

Xu Q, Du X, Huang T, Zheng Y, Li Y, Huang D Biomolecules. 2022; 12(10).

PMID: 36291586 PMC: 9599896. DOI: 10.3390/biom12101378.


E-cadherin is a robust prognostic biomarker in colorectal cancer and low expression is associated with sensitivity to inhibitors of topoisomerase, aurora, and HSP90 in preclinical models.

Bruun J, Eide P, Bergsland C, Bruck O, Svindland A, Arjama M Mol Oncol. 2021; 16(12):2312-2329.

PMID: 34890102 PMC: 9208074. DOI: 10.1002/1878-0261.13159.


Tumor Inhibitory Effect of Long Non-coding RNA LOC100505817 on Gastric Cancer.

Zheng L, Kang L, Cheng Y, Cao J, Liu L, Xu H Pathol Oncol Res. 2021; 27:581542.

PMID: 34385891 PMC: 8354317. DOI: 10.3389/pore.2021.581542.


Multi gene mutation signatures in colorectal cancer patients: predict for the diagnosis, pathological classification, staging and prognosis.

Zhuang Y, Wang H, Jiang D, Li Y, Feng L, Tian C BMC Cancer. 2021; 21(1):380.

PMID: 33836681 PMC: 8034139. DOI: 10.1186/s12885-021-08108-9.


References
1.
Berg M, Hagland H, Soreide K . Comparison of CpG island methylator phenotype (CIMP) frequency in colon cancer using different probe- and gene-specific scoring alternatives on recommended multi-gene panels. PLoS One. 2014; 9(1):e86657. PMC: 3897740. DOI: 10.1371/journal.pone.0086657. View

2.
Powell S, DeFrank J, Connell P, Eogan M, Preffer F, Dombkowski D . Differential sensitivity of p53(-) and p53(+) cells to caffeine-induced radiosensitization and override of G2 delay. Cancer Res. 1995; 55(8):1643-8. View

3.
Esposito C, Rachiglio A, La Porta M, Sacco A, Roma C, Iannaccone A . The S492R EGFR ectodomain mutation is never detected in KRAS wild-type colorectal carcinoma before exposure to EGFR monoclonal antibodies. Cancer Biol Ther. 2013; 14(12):1143-6. PMC: 3912037. DOI: 10.4161/cbt.26340. View

4.
Abraham R . Cell cycle checkpoint signaling through the ATM and ATR kinases. Genes Dev. 2001; 15(17):2177-96. DOI: 10.1101/gad.914401. View

5.
Montagut C, Dalmases A, Bellosillo B, Crespo M, Pairet S, Iglesias M . Identification of a mutation in the extracellular domain of the Epidermal Growth Factor Receptor conferring cetuximab resistance in colorectal cancer. Nat Med. 2012; 18(2):221-3. DOI: 10.1038/nm.2609. View