Anti-EGFR therapeutic efficacy correlates directly with inhibition of STAT3 activity

Abstract

Several agents targeting the epidermal growth factor receptor (EGFR) have been FDA-approved to treat cancer patients with varying tumor types including metastatic colorectal cancer. Many patients treated with anti-EGFR therapy however do not respond and those that do initially respond often acquire resistance. Here we show a clear correlation between the efficacy of anti-EGFR inhibitors with their ability to inhibit STAT3 activity in A431 epidermoid carcinoma cells and in a series of wt K-RAS expressing human colon cancer cell lines. Furthermore, the ability of cetuximab to inhibit growth also correlated with its ability to inhibit STAT3 activity in tumor xenograft animal studies. In addition, stable knockdown of the STAT3 phosphatase, protein tyrosine phosphatase receptor delta (PTPRD) resulted in enhanced STAT3 activity and subsequent resistance to cetuximab in DIFI colon carcinoma cells. This resistance could be reversed by STAT3 inhibition. Finally, HN5 cells with acquired resistance to the EGFR tyrosine kinase inhibitor, AG1478 displayed greater STAT3 activity than the HN5 control cell line. These AG1478-refractory HN5 cells were re-sensitized to AG1478, cetuximab and erlotinib when co-treated with a STAT3 inhibitor. Taken together, our current data indicates a key role of STAT3 activity in promoting resistance to anti-EGFR therapy and suggests that anti-EGFR therapy in combination with inhibitors that block STAT3 may provide therapeutic benefit for patients with mCRC and other EGFR driven tumor types.

Let-7a enhances the sensitivity of hepatocellular carcinoma cells to cetuximab by regulating STAT3 expression

“…In particular, patients who develop cetuximab resistance always have overexpression of STAT3 21. Furthermore, a novel STAT3 inhibitor NSC 74859 enhances the antiproliferative activity of cetuximab in HCC 22.…”

Cellular Signaling Pathways Implicated in Metastasis of Colorectal Cancer and the Associated Targeted Agents

“…Embelin, an X-linked inhibitor of apoptosis protein, is demonstrated to inhibit the colonic IL-6 expression as well as IL-6-induced STAT3 activation, thereby leading to the reduced tumorigenesis in colitisassociated cancer model [77]. Anti-EGFR agents like cetuximab approved for clinical treatment of metastatic CRC exhibit increased efficacy and decreased resistance when used in combination with STAT3 inhibitors [78]. Camptothecin and oxaliplatin, two clinically chemotherapeutic agents, display excellent efficacy in the treatment of malignancies including metastatic CRC.…”

The Frequency and Type of K-RAS Mutations in Mexican Patients With Colorectal Cancer

“…8 Therapy with these MAbs is only useful in the absence of K-RAS gene mutations, given the fact that when they block EGFR, they inhibit STAT3 activity and suppresses the stimulus of neoplastic cell proliferation. 9 In contrast, when K-RAS is mutated, it does not require EGF to exercise its stimulating effects of proliferation and therefore MAbs are useless. 10 This therapeutic method in mCRC produces a better response rate and, consequently, a higher survival time; therefore, molecular characterization of the neoplasia guides the use of the directed immunotherapy.…”