Titre

Inhibition of Haspin Kinase Promotes Cell-Intrinsic and Extrinsic Antitumor Activity.

Type
article
Institution
UNIL/CHUV/Unisanté + institutions partenaires
Périodique
Auteur(s)
Melms, J.C.
Auteure/Auteur
Vallabhaneni, S.
Auteure/Auteur
Mills, C.E.
Auteure/Auteur
Yapp, C.
Auteure/Auteur
Chen, J.Y.
Auteure/Auteur
Morelli, E.
Auteure/Auteur
Waszyk, P.
Auteure/Auteur
Kumar, S.
Auteure/Auteur
Deming, D.
Auteure/Auteur
Moret, N.
Auteure/Auteur
Rodriguez, S.
Auteure/Auteur
Subramanian, K.
Auteure/Auteur
Rogava, M.
Auteure/Auteur
Cartwright, ANR
Auteure/Auteur
Luoma, A.
Auteure/Auteur
Mei, S.
Auteure/Auteur
Brinker, T.J.
Auteure/Auteur
Miller, D.M.
Auteure/Auteur
Spektor, A.
Auteure/Auteur
Schadendorf, D.
Auteure/Auteur
Riggi, N.
Auteure/Auteur
Wucherpfennig, K.W.
Auteure/Auteur
Sorger, P.K.
Auteure/Auteur
Izar, B.
Auteure/Auteur
Liens vers les personnes
Liens vers les unités
ISSN
1538-7445
Statut éditorial
Publié
Date de publication
2020-02-15
Volume
80
Numéro
4
Première page
798
Dernière page/numéro d’article
810
Peer-reviewed
Oui
Langue
anglais
Notes
Publication types: Journal Article
Publication Status: ppublish
Résumé
Patients with melanoma resistant to RAF/MEK inhibitors (RMi) are frequently resistant to other therapies, such as immune checkpoint inhibitors (ICI), and individuals succumb to their disease. New drugs that control tumor growth and favorably modulate the immune environment are therefore needed. We report that the small-molecule CX-6258 has potent activity against both RMi-sensitive (RMS) and -resistant (RMR) melanoma cell lines. Haspin kinase (HASPIN) was identified as a target of CX-6258. HASPIN inhibition resulted in reduced proliferation, frequent formation of micronuclei, recruitment of cGAS, and activation of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway. In murine models, CX-6258 induced a potent cGAS-dependent type-I IFN response in tumor cells, increased IFNγ-producing CD8 <sup>+</sup> T cells, and reduced Treg frequency in vivo. HASPIN was more strongly expressed in malignant compared with healthy tissue and its inhibition by CX-6258 had minimal toxicity in ex vivo-expanded human tumor-infiltrating lymphocytes (TIL), proliferating TILs, and in vitro differentiated neurons, suggesting a potential therapeutic index for anticancer therapy. Furthermore, the activity of CX-6258 was validated in several Ewing sarcoma and multiple myeloma cell lines. Thus, HASPIN inhibition may overcome drug resistance in melanoma, modulate the immune environment, and target a vulnerability in different cancer lineages. SIGNIFICANCE: HASPIN inhibition by CX-6258 is a novel and potent strategy for RAF/MEK inhibitor-resistant melanoma and potentially other tumor types. HASPIN inhibition has direct antitumor activity and induces a favorable immune microenvironment.
PID Serval
serval:BIB_2F60306E9605
DOI
PMID
WOS
Permalien
Date de création
2020-01-03T20:40:53.164Z
Date de création dans IRIS
2025-05-20T20:43:47Z