1651P - Sphingosine kinase 1 (SPHK1) overexpression contributes to cetuximab resistance in human colorectal cancer models

Date 30 September 2012
Event ESMO Congress 2012
Session Poster presentation II
Topics Colon and Rectal Cancer
Translational Research
Basic Principles in the Management and Treatment (of cancer)
Presenter Luigi Formisano
Authors L. Formisano1, L. Nappi2, R. Rosa3, V. Damiano4, R. Marciano2, C. D'Amato4, C. Carlomagno4, G. Troncone5, S. De Placido4, R. Bianco4
  • 1Endocrinologia Ed Oncologia Molecolare E Clinica, University Federico II, 80131 - Napoli/IT
  • 2Medical Oncology, University Federico II, 80131 - Napoli/IT
  • 3University Federico II, Napoli/IT
  • 4Medical Oncology, University Federico II, Napoli/IT
  • 5Surgical Pathology, Università Federico II, Napoli/IT



Although the anti-Epidermal Growth Factor (EGFR) monoclonal antibody (mAb) 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 signalling pathways have been described. Experimental design: In this study, we investigated SphK1 contribution to cetuximab resistance in colorectal cancer in preclinical in vitro/in vivo models and in tumor specimens from patients.


Immunohistochemical analysis on colorectal cancer tissues revealed a correlation between SphK1 expression and K-Ras mutations. Moreover, 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 (DMS) or silencing via siRNA in resistant cells restores sensitivity to cetuximab, whereas exogenous SphK1 overexpression in sensitive cells confers resistance to these agents. Finally, treatment of resistant cells with fingolimod (FTY720), a S1P receptor (S1PR) inhibitor, resulted in re-sensitization to cetuximab both in vitro and in vivo, with significant inhibition of tumor growth, interference with signal transduction, induction of cancer cells apoptosis and prolongation of mice survival.


Our data could contribute to clarify SphK1 role in cetuximab resistance and may suggest SphK1 inhibition as a part of novel targeting strategies potentially effective also in resistant colorectal cancer patients.


All authors have declared no conflicts of interest.