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J.P. Loftus et al.
tions. This observation extended to a control non-KMT2A-R infant ALL model with a TCF3-PBX1 fusion from t(1;19), which had a concomitant KRAS muta- tion and was also insensitive to ENTO. Prior studies have shown that RAS mutations occur significantly more fre- quently in infants with B-ALL, particularly in those with the most common KMT2A-AFF1 subtype. Data do not agree as to whether ALL-associated RAS mutations confer higher relapse risk and inferior overall survival.8,24,57,58
The potential role of RAS mutations in conferring insen- sitivity to SYK inhibition in ALL was further extended by evaluation of ENTO in combination with the clinically- available MEK inhibitor selumetinib in two KMT2A-R ALL PDX models. As predicted,40,59 we observed signifi- cant inhibition of leukemia proliferation with SEL treat- ment of a RAS-mutant KMT2A-AFF1 infant ALL model with superior activity of ENTO and SEL combination. However, SEL monotherapy and combined SEL/ENTO therapy was also quite efficacious in a RAS wild-type KMT2A-AFF1 adult ALL model with high basal pERK lev- els. These data contrast somewhat with earlier preclinical data from Irving et al. demonstrating preferential activity of SEL (monotherapy or in combination with dexametha- sone) in RAS-mutant ALL,40,46 an approach now under clin- ical investigation in children with relapsed/refractory RAS-mutant ALL via the SeluDex phase I/II trial (clinicaltri- als.gov identifier: NCT03705507), but are concordant with data from Kerstjens et al. reporting preclinical MEK inhibitor activity in both RAS-mutant and wild-type ALL.59 Cremer et al. also recently reported that MAPK pathway activation is a major mechanism of entospletinib or fostamatinib resistance in AML and can be overcome with dual SYK and MEK inhibition.60
In summary, our studies show constitutive activation of SYK and associated kinase signaling in preclinical infant KMT2A-R and childhood Ph-like ALL PDX models. We report potent in vitro and in vivo effects of selective SYK inhibition with enhanced activity with chemotherapy in non-RAS-mutant KMT2A-R ALL models. We also observed combinatorial activity of ENTO with the MEK inhibitor selumetinib in two KMT2A-R ALL PDX models with RAS mutation or pathway activation. Our findings warrant further evaluation of efficacy and toxicity of ENTO/SEL dual therapy in additional PDX models, poten- tially in combination with steroids or other traditional chemotherapy agents. Taken together, our preclinical studies demonstrate activity of ENTO in KMT2A-R ALL in combination with anti-ALL chemotherapy or MEK inhibition and suggest a potential for clinical evaluation of SYK inhibitor-based therapies in children and adults with these high-risk leukemias.
Disclosures
AY, MW, AS and ST are current or former employees of
Gilead Sciences and have equity ownership in Gilead Sciences. SKT received research funding from Gilead Sciences. The remaining authors declare no relevant conflicts of interest.
Contributions
JPL and AY designed and performed research, analyzed data, and contributed to writing the manuscript; PAB contributed vital new reagents, and analyzed and interpreted data; LMN, AB, MW and AS performed research and analyzed data; ST and SKT oversaw the study, designed research, analyzed and inter- preted data, and wrote the manuscript; SKT was responsible for revision of the manuscript; all authors approved the final version of the manuscript.
Acknowledgments
We acknowledge Dr Ann Forslund and Ms Chelsea Mullins formerly at Gilead Sciences for study protocol management and data analysis, and Dr Emer Clarke at ReachBio Research Labs for assistance with experimental studies. We also thank Dr Christian Hurtz at the University of Pennsylvania for assistance with experimental studies and scientific discussion. These studies were supported by Gilead Sciences. Specimen banking for patients enrolled on the COG AALL0631 trial (clinicaltrials.gov identifier: NCT00557193) was supported by NIH/NCI U10CA180886 and U10CA098543. Infant and childhood ALL patient-derived xenograft model creation was also supported by the Gabrielle’s Angel Foundation for Cancer Research Foundation, the Rally Foundation for Childhood Cancer Research, the SchylerStrong Foundation in memory of Schyler Anna Herman, the Simutis family childhood leukemia research fund in memory of Andrew David Simutis, and Team Nate and the Viands family childhood leukemia research fund in honor of Nathaniel J Viands. LMN was supported by NIH/NCI 5T32HD43021-15. SKT was supported by NIH/NCI K08CA184418 and 1U01CA232486 awards and Department of Defense Translational Team Science Award CA180683P1.
Funding
These studies were supported by Gilead Sciences. Specimen banking for patients enrolled on the COG AALL0631 trial ((clinicaltrials.gov identifier: NCT00557193) was supported by NIH/NCI U10CA180886 and U10CA098543. Infant and childhood ALL patient-derived xenograft model creation was also supported by the Gabrielle’s Angel Foundation for Cancer Research Foundation, the Rally Foundation for Childhood Cancer Research, the SchylerStrong Foundation in memory of Schyler Anna Herman, the Simutis family childhood leukemia research fund in memory of Andrew David Simutis, and Team Nate and the Viands family childhood leukemia research fund in honor of Nathaniel J Viands. LMN was supported by NIH/NCI 5T32HD43021-15. SKT was supported by NIH/NCI K08CA184418 and 1U01CA232486 awards and Department of Defense Translational Team Science Award CA180683P1.
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