207P - KRAS mutational status and oxaliplatin sensitivity: the other side of the moon?

Date 30 September 2012
Event ESMO Congress 2012
Session Poster presentation II
Topics Biomarkers
Presenter Armando Orlandi
Authors A. Orlandi1, M. Di Salvatore1, M. Basso1, C. Bagalà1, A. Strippoli1, A. Calegari1, C. Pozzo2, A. Astone3, A. Cassano1, C. Barone1
  • 1Unit Of Medical Oncology, Catholic University of Sacred Heart, 00168 - Rome/IT
  • 2Dept. Medical Oncology, Catholic University of Sacred Heart, 00168 - Rome/IT
  • 3Policlinico A. Gemelli, Oncologia Medica, Catholic University of Sacred Heart, 00168 - Rome/IT

Abstract

Background

Oxaliplatin is a milestone of colorectal cancer therapy, but it is still lacking of a validated predictive biomarker of response. In a recent retrospective study we found a greater efficacy of oxaliplatin in KRAS mutated patients with metastatic colorectal cancer. Aim of the present study is to investigate “in vitro” the molecular basis of this finding and the possible role of ERCC1, the main mechanism of oxaliplatin resistance.

Methods

We selected four colorectal cancer cell lines, two KRAS wild type (wt)(HCT-8, HT-29) and two KRAS mutated (mt)(SW620, SW480). The sensitivity of these cell lines to oxaliplatin was evaluated by MTT-test. ERCC1 levels before and after exposure to oxaliplatin were determined by RT-PCR. KRAS was silenced in a KRAS mt cell line (SW620) in order to evaluate the effect on oxaliplatin sensitivity and on ERCC1 levels. ERCC1 was also silenced in all cell lines to confirm his role in the KRAS-mediated oxaliplatin resistance pathway.

Results

KRAS mt cell lines were more sensitive to oxaliplatin (OR 2,68; IC 95% 1.511-4.757 p < 0.001). KRAS mt and wt cell lines did not show significant differences in ERCC1 basal levels, however, after 24h exposure to oxaliplatin, only resistant KRAS wt cell lines showed a statistically significant upregulation of ERCC1 compared to KRAS mt cell lines (OR 42.9; IC 95% 17.260-106.972 p < 0.0005). Silencing of KRAS demonstrated to reduce Oxaliplatin sensitivity and to restore the ability to induce ERCC1 in KRAS mt cell lines. Finally, silencing of ERCC1 increased Oxaliplatin citotoxicity only in those cells able to upregulate ERCC1 after exposure to Oxaliplatin, that is KRAS wt and KRAS mt/KRAS silenced colorectal cancer cell lines.

Conclusions

KRAS mt cell lines were more sensitive to oxaliplatin probably due to their inability to upregulate ERCC1 after exposure to this drug. Therefore, KRAS mutational status could represent a predictor of response to Oxaliplatin in colorectal cancer patients, as a surrogate for ERCC1 modulation.

Disclosure

All authors have declared no conflicts of interest.