Abstract We previously developed and reported a novel laboratory-derived chemotherapeutic regimen of capecitabine and temozolomide (TMZ) (CapTem). The CapTem regimen is highly active, well-tolerated with minor toxicities and may prolong survival and palliate symptoms in patients with well differentiated neuroendocrine tumors (NET). Further studies with CapTem in our laboratory indicated that sunitinib, a tyrosine kinase inhibitor (TKI), was highly synergistic with 5-Fluorouracil (5-FU) in killing BON (NET) cells. (Capecitabine is enzymatically converted to 5-FU in the tumor). Synergy was observed at a low concentration of 1.0 μM 5-FU and 1 nM sunitinib. Addition of 100 nM sunitinib resulted in a 4.5 fold increase in cell death (14.2 vs 64.5%). In addition, if sunitinib was combined with the CapTem regimen, (5-FU followed by TMZ), a synergistic response was observed with both 5-FU and TMZ over a range of concentrations, giving a maximal cell death of 74.4%. This contrasts with the cell death obtained with 5-FU, TMZ and sunitinib alone, resulting in 9.0, 6.8 and 10.2% annexin V+ cells, respectively. Sorafinib, a TKI closely related to sunitinib, not only did not synergize with 5-FU or TMZ, it inhibited cell death observed with sunitinib and 5-FU/ TMZ. In addition, K-252a, a potent inhibitor of tyrosine kinases, reduced the cell death induced by 5-FU/sunitinib suggesting a tyrosine kinase was involved. Considering the IC-50 of sunitinib for PDGF β is 75 nM, whereas for sorafinib it is 1129 nM, a difference of 15 fold, we hypothsized that the PDGF-β pathway might be involved. Addition of the PDGF-ββ form resulted in an enhancement of 5-FU/TMZ (CapTem) cell death. However, there was no effect on sunitinib-induced cell death, suggesting that the PDGF-β pathway may be involved but to an unknown extent in the cell death pathway induced by CapTem. Exposure of BON cells to TMZ and 5-FU may mimic the in vivo exposure to these drugs in patients and the resulting cell line resistance may be similar to resistance in tumors. Preliminary studies with four resistant BON cell lines: TMZ-Resistant, 5-FU-Resistant, TMZ+5FU-Resistant, (concurrent exposure to TMZ and 5-FU) and TMZ -> 5FU-Resistant, (sequential exposure to 5FU and TMZ) found that cells resistant to CapTem still retain sensitivity to sunitinib. This suggests that addition of sunitinib can overcome CapTem resistance in BON cells. Citation Format: Richard D. Dinnen, Yuehua Mao, Daniel P. Petrylak, Robert L. Fine. Synergistic combinations of targeted therapy and chemotherapy for neuroendocrine cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 910. doi:10.1158/1538-7445.AM2013-910