Highlights of This Issue

Abstract

TRAIL is a potent inductor of apoptosis through activation of death receptors overexpressed on tumor cells. To improve the cytotoxic activity of TRAIL, Seifert and colleagues applied the IgE heavy-chain domain 2 (EHD2) as covalently linked homodimerization module to generate a tetravalent and bifunctional molecule by fusing an scFv to the N-terminus and a single-chain derivative of TRAIL to the C-terminus of the EHD2, combining target cell selectivity with an increased TRAIL activity. The fusion protein exhibited improved antitumor activities in vitro and in vivo and established the EHD2 as a versatile building block for the generation of targeted multivalent and multifunctional protein therapeutics.Clinically, BRAF-mutated melanoma tumors often develop acquired resistance to vemurafenib through several pathways. Effective drug combination strategies are highly desirable to overcome this resistance. Wang and colleagues discovered previously that vemurafenib-resistant cells escape G0–G1 cell-cycle arrest. Here, they demonstrated that combination of vemurafenib with a novel tubulin inhibitor, ABI-274, synergistically arrested melanoma cells in vitro and induced tumor regression in a vemurafenib-resistant xenograft model in vivo. The study offers a potential therapeutic strategy to overcome vemurafenib resistance mediated by RTK-driven PI3K pathway activation, and delay the development of vemurafenib resistance in patients.Acquired and intrinsic resistance to HER2 kinase inhibitors such as lapatinib presents a significant challenge for HER2-overexpressing breast cancers. Here, Brady and colleagues show that upregulation and/or mutation of PI3K p110α can promote acquired lapatinib resistance. The PI3K p110β isoform was dispensable for lapatinib resistance in their models. Lapatinib combined with the p110α-selective PI3K inhibitor BYL719 overcame lapatinib resistance in vitro and in animal xenografts, with minimal toxicity. These findings provide the basis for testing p110α-specific PI3K inhibition in patients to overcome lapatinib resistance and minimize the toxicity of pan-PI3K inhibitors, thus allowing maximal dosage and efficacy.Cross-talk between HER2 and IGF-IR and elevated IGF-IR signaling may contribute to resistance to trastuzumab (Herceptin; Genentech) therapy targeting HER2. Chen and colleagues developed bispecific antibody against HER2 and IGF-IR (Bi-Ab). The Bi-Ab alone or in combination with monospecific antibodies showed superior antitumor activity in vitro and in vivo compared with monospecific antibodies alone. The treatment of Bi-Ab resulted in extensive and sustainable tumor regression in SKOV-3 cancer xenografts overexpressed with HER2- and IGF-IR. This study indicates that cotargeting two or more tumor-associated cell surface receptors by bispecific antibodies may be clinically beneficial in minimizing acquired resistance to monospecific antibody therapies.