Mechanisms mediating the negative interaction between oxaliplatin (Ox) and epidermal growth factor receptor (EGFR) inhibitors in patients (pts) with KRAS mutant (MT) colorectal cancer (CRC).

3580 Background: Phase 3 trials have shown that pts with MT KRAS tumors have shorter progression-free survival and overall survival when an EGFR inhibitor is added to Ox-containing chemotherapy (CT) (Bokemeyer et al 2011, Douillard et al 2010). However, KRAS status alone is not predictive of pt outcomes in this setting. The negative interaction has not been observed in pts with wild-type (WT) KRAS tumors receiving an EGFR inhibitor and platinum-CT or with MT KRAS tumors receiving an EGFR inhibitor with irinotecan (Peeters et al 2010, Van Cutsem et al 2009). Our goal was to understand the pharmacodynamic interaction between EGFR inhibitors and Ox in KRAS MT 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. Down...