Silencing of miR-338-5p/-421 Drives SPINK1-Positive Cancer
Bhatia et al., p. 2755
Increased SPINK1 levels associate with poor clinical outcome and represent the second-largest molecular subtype of prostate cancer. Bhatia and colleagues deciphered the mechanism of SPINK1 upregulation and established a regulatory model, showing the functional interplay between SPINK1, miRNA-338-5p/miRNA-421 and EZH2. In this study, the authors show that overexpression of miRNA-338-5p/miRNA-421 in SPINK1-positive cancer cells attenuates its oncogenic properties, tumorigenesis, and metastases. In agreement, SPINK1-postive prostate cancer patients show epigenetic silencing of miRNA-338-5p/miRNA-421 due to increased levels of EZH2. This study opens avenues for the use of epigenetic drugs or synthetic mimics of miRNA-338-5p/miRNA-421 as an adjuvant therapy for SPINK1-positive malignancies.
D-1347 for Advanced Solid Tumors with FGFR Gene Alterations
Voss et al., p. 2699
Fibroblast growth factor receptors (FGFR), in their function as upstream tyrosine kinases activating the MAPK and the PI3K signaling pathways, can regulate cellular growth and have established roles in human tumorigenesis. In that setting, increased kinase signaling can be brought about by a variety of genetic alterations which can be detected in patient tumor samples, identifying those patients most likely to benefit from FGFR-directed therapy. In the present phase I trial, Voss and colleagues investigate the safety and efficacy of Debio 1347, a highly selective orally available FGFR 1-3 inhibitor, in a target population of patients that screened positive for harboring activating FGFR1-3 alterations in their tumors. This approach proved to be feasible with promising tolerability and efficacy results.
LAMP5 Regulates MLL Fusion Protein Degradation in Leukemia
Wang et al., p. 2795
Because of the development of resistance and high-relapse rates with currently available therapies, mixed-lineage leukemia (MLL leukemia) is frequently associated with a poor prognosis; therefore, novel therapeutic targets are urgently needed. Wang and colleagues discovered that LAMP5 is a novel autophagic suppressor, is specifically expressed in MLL leukemia, and serves as a bodyguard for fusion proteins to evade degradation. Suppressing LAMP5 expression effectively released MLL fusions from its defence system and extended survival in vivo. This effect was particularly strong when combining DOT1L inhibitors and LAMP5 knockdown. The finding highlights the potential of LAMP5 as a therapeutic target.
SFN Blocks Ubiquitination of Oncoproteins in Lung Cancer
Shiba-Ishii et al., p. 2809
Aberrant overexpression of stratifin (SFN) can be detected in lung adenocarcinoma from an early stage, playing a role in oncogenesis and progression. Shiba-Ishii and colleagues identify SKP1 as an SFN binding partner and demonstrate that SFN-SKP1 binding causes dysfunction of a specific ubiquitin ligase, SCFFBW7, allowing several oncoproteins to evade ubiquitination and degradation. In silico drug screening selected aprepitant and ticagrelor as potential SFN inhibitors that dose-dependently reduced SFN-SKP1 binding and tumor progression. Because SFN is widely expressed from an early stage, these drugs would be promising candidates for nonsurgical treatment of advanced and early-stage tumors.