Highlights of This Issue Free

FGF19 is a postprandial hormone released by the ileum that has been identified as a driver gene for hepatocellular cancer (HCC). Based on its unique specificity for FGFR4, A. Weiss, D. Graus-Porta and colleagues hypothesized that a selective FGFR4 inhibitor could be developed for use in HCC. The result was FGF401, a first-in-class FGFR4 inhibitor with high potency and selectivity. FGF401 inhibited the growth of cell lines and their xenografts that co-express FGF19, FGFR4, and the co-receptor KLB. Furthermore, FGF401 demonstrated activity in five FGF19/FGFR4/KLB-expressing patient derived xenografts (four HCC, one gastric). FGF401 therefore represents a formative FGFR4-selective inhibitor and is the first to enter clinical trials (NCT02508467).

Metastatic renal and bladder cancers remain challenged by low 5-year survival rates. Cabozantinib, a multi-target tyrosine kinase inhibitor (TKI), showed significant clinical benefit in metastatic renal cancer during the phase 3 METEOR study (second line) and phase 2 CABOSUN study (first line). Cabozantinib also has the advantage in modulating tumor immunity, thereby creating a tumor environment more suited for checkpoint inhibition. In this article, Bergerot and colleagues review the efforts to combine cabozantinib with immunotherapy in metastatic renal and bladder cancer. They begin by providing the rationale for this combination, and then overview the preclinical and clinical results.

Inhibition of the Aurora A kinase leads to mitotic spindle formation defects and results in cell death. However, any non-specific significant activity against Aurora B or C leads instead to polyploidy and detracts from the anti-neoplastic effects of the Aurora A inhibitor. In this manuscript, Du and colleagues outline the anti-tumor effects of the Aurora A-specific kinase inhibitor LY3295668. LY3295668 showed sub-micromolar IC50 values in a wide array of cell lines, including small cell lung cancer (SCLC) and triple-negative breast cancer. LY3295668 reduced tumor volumes in patient-derived xenografts of SCLC. Taken together, LY3295668 has distinct Aurora A potency and selectivity that contrasts with currently developed Aurora A/B inhibitors (alisertib, barasertib).

Despite the design of third generation tyrosine kinase inhibitors (TKIs) for non-small cell lung cancer (NSCLC) patients with EGFR T790M-positive tumors, acquired resistance remains an issue. Previous studies have linked integrin expression to this resistance, although none have determined the specific subtype. In this manuscript, Wang and colleagues determine that the integrin β3 axis uniquely contributes EGFR TKI resistance in NSCLC. They demonstrate TGF-β activates integrin β3, generating a survival advantage. Antagonizing integrin β3 reduced EMT and invasion and increased NSCLC sensitivity to osimertinib or gefitinib. Although previous clinical developments of integrin inhibitors have failed, this study provides new specificity to design effective mitigation of EGFR TKI resistance.