Sphingosine Kinase 1 Overexpression Contributes to Cetuximab Resistance in Human Colorectal Cancer Models

Abstract

Purpose: Although the anti-EGF receptor (EGFR) monoclonal antibody cetuximab is an effective strategy in colorectal cancer therapy, its clinical use is limited by intrinsic or acquired resistance. Alterations in the "sphingolipid rheostat"-the balance between the proapoptotic molecule ceramide and the mitogenic factor sphingosine-1-phosphate (S1P)-due to sphingosine kinase 1 (SphK1) overactivation have been involved in resistance to anticancer-targeted agents. Moreover, cross-talks between SphK1 and EGFR-dependent signaling pathways have been described.Experimental design: We investigated SphK1 contribution to cetuximab resistance in colorectal cancer, in preclinical in vitro/in vivo models, and in tumor specimens from patients.Results: SphK1 was found overexpressed and overactivated in colorectal cancer cells with intrinsic or acquired resistance to cetuximab. SphK1 contribution to resistance was supported by the demonstration that SphK1 inhibition by N,N-dimethyl-sphingosine or silencing via siRNA in resistant cells restores sensitivity to cetuximab, whereas exogenous SphK1 overexpression in sensitive cells confers resistance to these agents. Moreover, treatment of resistant cells with fingolimod (FTY720), a S1P receptor (S1PR) antagonist, resulted in resensitization to cetuximab both in vitro and in vivo, with inhibition of tumor growth, interference with signal transduction, induction of cancer cells apoptosis, and prolongation of mice survival. Finally, a correlation between SphK1 expression and cetuximab response was found in colorectal cancer patients.

Deregulation of the PP2A Inhibitor SET Shows Promising Therapeutic Implications and Determines Poor Clinical Outcome in Patients with Metastatic Colorectal Cancer

“…The KRAS-mutated status is a very high prevalent alteration in mCRC that determines resistance to the monoclonal antibody cetuximab. Interestingly, it has recently reported that FTY720 could resensitize colorectal cancer cells to cetuximab, indicating a potential therapeutic relevance for FTY720 in mCRC (38). Of importance, when we stratify our series by the KRAS mutation status, the SET prognostic impact was particularly strong in those patients with KRAS-mutated (P < 0.001; Supplementary Fig.…”

Inhibition of Insulin-like Growth Factor–Binding Protein-3 Signaling through Sphingosine Kinase-1 Sensitizes Triple-Negative Breast Cancer Cells to EGF Receptor Blockade

“…The growth of MDA-MB-468 xenograft tumors was shown to be inhibited by ABC294640, an SphK2-specific inhibitor, when used as a single-line agent (45). Acquired resistance to chemotherapeutic drugs, hormonal therapies, and growth factor receptor inhibitors, including EGFR inhibitors, has been linked with overexpression of SphK1 in a number of malignancies (46)(47)(48)(49)(50), providing a clear rationale for the use of SphK1 inhibitors in the clinic as adjuvant therapies. Our study has shown potent antiproliferative effects of dual inhibition of EGFR and SphK1 in cell lines representing a subset of breast cancers for which there is currently a paucity of treatments, and has demonstrated in a preclinical study proof-of-principle that this combination has therapeutic potential.…”

FTY720 for cancer therapy (Review)

“…Recent studies shed further insight into the mode of action of FTY720 by demonstrating that it directly inhibits SphK1 activity both in vitro and in vivo. For instance, FTY720 could resensitize human colorectal cancer to cetuximab by inhibiting SphK1 both in vitro and in vivo, with inhibition of tumor growth, interference with signal transduction, induction of cancer cell apoptosis, and prolongation of mouse survival (91). In addition to directly inhibiting SphK1 activity, FTY720 has been demonstrated to induce SphK1 degradation via ubiquitination and subsequent proteasomal processing (93); however, the precise mechanism has not been defined.…”