ATM mutations and E-cadherin expression define sensitivity to EGFR-targeted therapy in colorectal cancer

作者：Geissler Anna Lena; Geissler Miriam; Kottmann Daniel; Lutz Lisa; Fichter Christiane D; Fritsch Ralph; Weddeling Britta; Makowiec Frank; Werner Martin; Lassmann Silke^*

来源：Oncotarget, 2017, 8(10): 17164-17190.

DOI：10.18632/oncotarget.15211

• anti-EGFR therapy
• next generation sequencing
• predictive markers
• colorectal cancer (CRC)
• E-cadherin

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 (Caco2, 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.

• 出版日期2017-3-7