The molecular interaction pattern of lenvatinib enables inhibition of wild-type or kinase-mutated FGFR2-driven cholangiocarcinoma.

Fibroblast growth factor receptor (FGFR)-2 can be inhibited by FGFR-selective or non-selective tyrosine kinase inhibitors (TKIs). Selective TKIs are approved for cholangiocarcinoma (CCA) with FGFR2 fusions; however, their application is limited by a characteristic pattern of adverse events or evocation of kinase domain mutations. A comprehensive characterization of a patient cohort treated with the non-selective TKI lenvatinib reveals promising efficacy in FGFR2-driven CCA. In a bed-to-bench approach, we investigate FGFR2 fusion proteins bearing critical tumor-relevant point mutations. These mutations confer growth advantage of tumor cells and increased resistance to selective TKIs but remain intriguingly sensitive to lenvatinib. In line with clinical observations, in-silico analyses reveal a more favorable interaction pattern of lenvatinib with FGFR2, including an increased flexibility and ligand efficacy, compared to FGFR-selective TKIs. Finally, the treatment of a patient with progressive disease and a newly developed kinase mutation during therapy with a selective inhibitor results in a striking response to lenvatinib. Our in vitro, in silico, and clinical data suggest that lenvatinib is a promising treatment option for FGFR2-driven CCA, especially when insurmountable adverse reactions of selective TKIs or acquired kinase mutations occur.

SNP array analysis of acute promyelocytic leukemia may be of prognostic relevance and identifies a potential high risk group with recurrent deletions on chromosomal subband 1q31.3.

To search for new copy number alterations (CNAs) in acute promyelocytic leukemia (APL), we analyzed DNA from leukemic blasts of 93 acute promyelocytic leukemia (APL) patients with Genome-Wide SNP 6.0 arrays (SNP-A). We identified 259 CNAs consisting of 170 heterozygous deletions, 82 amplifications, and 7 regions of copy number neutral loss of heterozygosity. One of the most common CNAs was a deletion on chromosomal subband 1q31.3 in 13 of 93 (14%) patients encompassing the coding regions for the microRNAs mir181a1/b1. In multivariable analysis with the covariates age, white blood cell count, platelet count, and FLT3-ITD/FLT3 D835 mutations we found that after adjustment for patients' age (P<0.0001), patients with 2 or more CNAs detected by SNP-A had a higher risk of death (hazard ratio=5.942, P=0.0015) than patients with 0 or 1 CNA. Deletions of 1q31.3 were associated with a higher number of CNAs (median 2 vs. 8, P<0.0001) and were a strong independent prognostic factor for an increased risk of relapse (hazard ratio=28.9, P=0.0031). This study presents a comprehensive assessment of new CNAs as pathomechanistically relevant targets and possible prognostic factors which could refine risk stratification of APL.