P-0199 Mechanisms Mediating The Negative Interaction Between Oxaliplatin and Epidermal Growth Factor Receptor Inhibitors in Patients With KRAS Mutant Colorectal Cancer

Abstract

ABSTRACT Introduction Platinum agents are a standard of care for the treatment of many cancers. Phase 3 trials have shown that patients (pts) with mutant (MT) KRAS tumors have shorter progression-free survival and overall survival when panitumumab or cetuximab is added to oxaliplatin (Ox)-containing chemotherapy (CT). This negative interaction has not been observed in pts with wild-type (WT) KRAS tumors receiving an epidermal growth factor receptor (EGFR) inhibitor and platinum-CT or with MT KRAS tumors receiving an EGFR inhibitor with irinotecan. Our goal was to understand the pharmacodynamic interaction between EGFR inhibitors and Ox in KRAS MT colorectal cancer (CRC) cells. Methods Isogenic MT and WT KRAS-expressing HCT116 CRC cells were treated with Ox, SN-38 (the active metabolite of irinotecan), panitumumab, gefitinib, or inhibitors of MEK, PI3K or Src as single agents or in combination. Viability was measured using an ATPlite assay. Cellular distribution of EGFR was visualized by a confocal microscopy. Downstream activation of MAPK and PI3K was detected by Western blotting. Results Treatment with gefitinib, but not panitumumab, reversed the anti-proliferative effects of Ox in the MT KRAS-expressing CRC cells vs Ox alone (p Conclusion Feedback though AKT may contribute to the increased resistance to Ox in KRAS MT cells. Inhibitors of MEK, PI3K, or Src reversed the negative interaction between the EGFR inhibitors and Ox in a MT-KRAS genetic background.