Home Blog of Signal Transduction ER stress & UPR JNK Targeting of BCR-ABL1 and IRE1α induces synthetic lethality in Philadelphia-positive acute lymphoblastic leukemia

Category

Archives

Popular Post

ESKM, a novel therapeutic agent for sensitive and resistant PH+ leukemias

The mechanism of resistance to JAK2 inhibitor in myeloproliferative neoplasms patients

Effects of PARP inhibitors in BRCA gene-mutated ovarian cancer

DASATINIB; An inhibitor of Receptor Tyrosine Kinase

GP130/JAK/STAT3 signaling pathway induces multiple myeloma

Targeting of BCR-ABL1 and IRE1α induces synthetic lethality in Philadelphia-positive acute lymphoblastic leukemia

BCR-ABL1-positive acute lymphoblastic leukemia (ALL) cell survival is dependent on the inositol requiring enzyme 1 alpha (IRE1α) branch of the unfolded protein response. In the current study, we have focused on exploring the efficacy of a simultaneous pharmacological inhibition of BCR-ABL1 and IRE1α in Philadelphia positive (Ph +) ALL, using tyrosine kinase inhibitor (TKI) nilotinib and the IRE1α inhibitor MKC-8866.The combination of 0.5 µM nilotinib and 30 µM MKC-8866 in Ph + ALL cell lines led to a synergistic effect on cell viability. To mimic this dual inhibition on a genetic level, pre-B cells from conditional Xbp1+/fl mice were transduced with a BCR-ABL1 construct and with either tamoxifen-inducible cre or empty vector. Cells showed a significant sensitization to the effect of TKIs after induction of the heterozygous deletion. Finally, we performed a phosphoproteomic analysis on Ph + ALL cell lines treated with the combination of nilotinib and MKC-8866 to identify potential targets involved in their synergistic effect. An enhanced activation of p38 mitogen-activated protein kinase α (p38α MAPK) was identified. In line with this findings, p38 MAPK, as well as another important ER-stress related kinase, c-Jun N terminal kinase (JNK) were found to mediate the potentiated cytotoxic effect induced by the combination of MKC-8866 and nilotinib, since the targeting of p38 MAPK with its specific inhibitor BIRB-796 or JNK with JNK-in-8 hindered the synergistic effect observed upon treatment with nilotinib and MKC-8866. In conclusion, the identified combined action of nilotinib and MKC-8866 might represent a successful therapeutic strategy in high-risk Ph + ALL.

Related Products

Cat.No. Product Name Information
S4901 JNK-IN-8 JNK-IN-8 (JNK Inhibitor XVI) is the first irreversible JNK inhibitor for JNK1, JNK2 and JNK3 with IC50 of 4.7 nM, 18.7 nM and 1 nM, >10-fold selectivity against MNK2, Fms and no inhibition to c-Kit, Met, PDGFRβin A375 cell line.

Related Targets

JNK