Zhihua Jiao, Hang Ke, Faming Zhang, Henry Li, Jessie Wang
Mantle cell lymphoma (MCL) is a subtype of non-Hodgkin lymphomas (NHL) of a mature B-cell malignance (~6% of NHLs), hallmarked with the chromosomal translocation t(11;14) and (q13;q32). MCL is considered difficult to treat, with frequent relapse after effective conventional chemotherapy, contributing to a short median survival (5-7 years) and thus warranting the development of new therapeutics. Although the recent approval of Bruton tyrosine Kinase inhibitor (BTKi) has greatly improved the treatment of MCL, patients who exhibit intrinsic or BTKi-induced resistance have few treatment options.
HX301 (ON123300) is a clinical-stage multi-kinase inhibitor (CDK4/6, ARK5 and PI3K-δ, etc.) shown to be potent against MCL via its dual targeting mechanism of action (MOA) against CDK4 and PI3K-δ (Table 1), as demonstrated through in vitro activities on two MCL cell lines (Granta519, Z138C), a couple of primary patient samples, and in vivo activity in a Z138C cell line-derived xenograft (CDX) model. In order to test the hypothesis that HX301 may have broad activity against MCL convincingly, we examined an expanded panel of preclinical MCL models, patient-derived xenograft (PDX), and BTKi-resistant tumors. Additionally, we have explored whether the combination of HX301 and BTKi (ibrutinib) could achieve improved suppression over the single agent (HX301 or ibrutinib)
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