Erlotinib targets the CBL mediated chemoresistance mechanism. A, when erlotinib (Erlot), a targeted EGFR inhibitor, was added in combination with Gem or 5-FU to cells with CBL knockdown, cell viability was significantly reduced (column 2 vs. 4 and 6 vs. 8, P<0.05), and comparable to the isogenic parental cell line (column 3 vs. 4 and 7 vs. 8). Error bars ± SD. B, utilizing immunoblot to investigate the underlying signaling mechanisms involved we observed that erlotinib inhibition of pEGFR Y1068 decreases pAKT signaling (columns 2 vs. 4) and enhances apoptosis as evidenced by increased cleaved PARP and caspase 3. Relative densitometry units normalized to β-actin are reported above each band. C, densitometry analysis comparing the ratio of pAKT/total AKT again highlights the inhibition of pAKT signaling by erlotinib even with CBL knockdown. D, likewise, a greater percentage of apoptotic cells were observed by Annexin V/PI FACS when CBL knockdown cells were treated with dual therapy Gem + erlotinib. Error bars ± SD.