Acute and chronic treatment of trametinib plus lapatinib in patient-derived xenografts (PDX) of pancreatic adenocarcinoma (PDAC)

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease with limited effective treatment options. PDAC tumors frequently harbor the constitutively activated form of KRAS which drives proliferative signaling, but directly targeting KRAS has so far been unsuccessful. To overcome this limitation, combinatorial treatment strategies have been developed to inhibit upstream activators and downstream effectors of KRAS signaling. One such combination using trametinib, a MEK1/2 inhibitor, and lapatinib, an EGFR/HER2 inhibitor, substantially reduced tumor growth in a patient-derived xenograft (PDX) model of PDAC. Although trametinib and lapatinib are both known to inhibit the canonical MAPK signaling cascade, the effects of this combination on other important pathways in pancreatic cancer remains unclear. To investigate this, we analyze global gene expression profiles from PDX models of PDAC treated with trametinib, lapatinib, or their combination. Our results show that trametinib induces similar yet less significant expression changes compared to combination while lapatinib has little to no effect as a monotherapy in the acute treatment setting. In the chronic treatment setting, we show that tumors exposured to prolonged treatment with trametinib plus lapatinib eventually leads to adapative resistance. Expression analyses of resistant tumors revealed concominant gene expression changes in upstream receptor tyrosine kinases (RTKs). Patient-derived xenografts (PDX) from patients with pancreatic adenocarcinoma (PDAC) were explanted onto the pancreata of nude mice to evaluate the effects of trametinib (a MEK inhibitor), lapatinib (an EGFR/HER2 inhibitor) after acute (24 hours) exposure and chronic (3 months) exposure. In a factorial design, tripliate samples were obtained from T366, T608, and T738 tumors treated acutely with trametinib (3 mg/kg) plus lapatinib (65 mg/kg), trametinib (3 mg/kg) alone, lapatinib (65 mg/kg) alone, or vehicle controls.