Several antagonistic IGF-1R monoclonal antibodies with differential IGF-blocking capability and receptor downregulation efficiency are in clinical development for solid tumors. Here Dong and colleagues report that combining two IGF-IR inhibitory antibodies with distinct epitopes and ligand-blocking mechanisms led to significantly improved ligand blockade and receptor downregulation, resulting in enhanced inhibition of IGF-IR signaling and tumor growth. Individual IGF-IR antibodies were also found to have limitations in their antitumor activity at high IGF levels, which can be overcome by the antibody combination. Their data suggest that antibodies targeting two distinct epitopes of IGF-IR may provide improved clinical efficacy.Development of drug resistance has been a growing concern for inhibitors of the class III receptor tyrosine kinase, FLT3, found in a subset of AML patients. Weisberg and colleagues identified the novel type II ATP competitive inhibitors, HG-7-85-01 and HG-7- 86-01, as highly potent and selective inhibitors of PKC412- sensitive and –resistant mutant FLT3 with the ability to synergize with PKC412 and standard chemotherapeutic agents. The ability of these compounds to inhibit mutant FLT3 is a distinctive feature that, in combination with demonstrated activity against a diverse panel of tyrosine kinase gatekeeper mutants, underscores their structural uniqueness and potential clinical versatility.Pancreatic cancer is a highly lethal malignancy driven by cancer stem cells (CSC). Rajeshkumar and colleagues identified a druggable target enriched in pancreatic CSCs (DR5). Gemcitabine, the first-line chemotherapeutic agent for pancreatic cancer, was ineffective in depleting CSCs and eventually culminated in tumor recurrence in pancreatic cancer xenografts. A combination of tigatuzumab, a fully humanized DR5 agonistic mAb, with gemcitabine resulted in remarkable reduction in pancreatic CSCs, tumor remissions, and long-term disease control in a model that is considered more difficult to treat. These findings have potential therapeutic implications for improving the current standard of care for pancreatic cancer patients.