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Ref Type Journal Article
PMID (29296813)
Authors Roberts KG, Yang YL, Payne-Turner D, Lin W, Files JK, Dickerson K, Gu Z, Taunton J, Janke LJ, Chen T, Loh ML, Hunger SP, Mullighan CG
Title Oncogenic role and therapeutic targeting of ABL-class and JAK-STAT activating kinase alterations in Ph-like ALL.
Journal Blood advances
Vol 1
Issue 20
Date 2017 Sep 12
URL
Abstract Text New therapies for Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) patients are urgently needed. The genetic landscape of Ph-like ALL is characterized by a diverse array of kinase-activating alterations (including rearrangements, sequence mutations, and copy number alterations), suggesting that patients with Ph-like ALL are candidates for targeted therapy, similar to BCR-ABL1 ALL. We sought to investigate the functional role and targetability of the spectrum of kinase-activating alterations identified in Ph-like ALL. We demonstrate cytokine-independent growth and activation of JAK-STAT signaling pathways in Ba/F3 cells by all alterations tested. The development of murine Arf-/- pre-B ALL expressing RCSD1-ABL2 or SSBP2-CSF1R was accelerated with the presence of IK6, a dominant negative isoform of Ikaros common in Ph-like ALL, providing evidence that these fusions are leukemogenic. In vitro screening using a panel of tyrosine kinase inhibitors against 14 different kinase alterations identified the ABL1-inhibitor, dasatinib, as a potent inhibitor of ABL-class fusions (ABL1, ABL2, CSF1R, PDGFRB), whereas the JAK1/JAK2 inhibitor ruxolitinib, was most effective against JAK-STAT-activating alterations (JAK1, JAK2, JAK3, IL7R, IL2RB), but not TYK2. Evaluation of dasatinib or ruxolitinib against patient-derived xenograft models demonstrated superior antileukemic efficacy when combined with dexamethasone compared with either agent alone. These data provide the foundation for rationally designed clinical trials that assess the efficacy of targeted therapy in patients with Ph-like ALL.

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Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Baricitinib Olumiant LY3009104|INCB028050|INCB 028050|LY 3009104 JAK1 Inhibitor - ATP competitive 5 JAK2 Inhibitor - ATP competitive 15 Baricitinib (LY3009104) is a selective inhibitor of JAK1, JAK2, and TYK2, which may decrease tumor cell viability (PMID: 20363976, PMID: 29399328, PMID: 29296813).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FLT3 exon 14 ins hematologic cancer sensitive Dovitinib Preclinical - Cell culture Actionable In a preclinical study, transformed cells harboring FLT3-ITD were sensitive to treatment with Dovitinib (TKI258) in culture, demonstrating decreased cell viability (PMID: 29296813). 29296813
FLT3 exon 14 ins hematologic cancer sensitive NVP-BSK805 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FLT3-ITD were sensitive to treatment with NVP-BSK805 in culture, demonstrating decreased cell viability (PMID: 29296813). 29296813
FLT3 exon 14 ins hematologic cancer sensitive NVP-BVB808 Preclinical - Cell culture Actionable In a preclinical study, transformed cells expressing FLT3-ITD were sensitive to treatment with NVP-BVB808 in culture, demonstrating decreased cell viability (PMID: 29296813). 29296813