1.BCR: a new target in resistance mediated by BCR/ABL-315I?
Haberbosch I1, Rafiei A2, Oancea C3, Ottmann GO4, Ruthardt M3, Mian AA3. Genes Cancer. 2016 Jan;7(1-2):36-46.
Targeting BCR/ABL with Tyrosine kinase inhibitors (TKIs) is a proven concept for the treatment of Philadelphia chromosome-positive (Ph+) leukemias but the "gatekeeper" mutation T315I confers resistance against all approved TKIs, with the only exception of ponatinib, a multi-targeted kinase inhibitor. Besides resistance to TKIs, T315I also confers additional features to the leukemogenic potential of BCR/ABL, involving endogenous BCR. Therefore we studied the role of BCR on BCR/ABL mutants lacking functional domains indispensable for the oncogenic activity of BCR/ABL. We used the factor independent growth of murine myeloid progenitor 32D cells and the transformation of Rat-1 fibroblasts both mediated by BCR/ABL. Here we report that T315I restores the capacity to mediate factor-independent growth and transformation potential of loss-of-function mutants of BCR/ABL. Targeting endogenous Bcr abrogated the capacity of oligomerization deficient mutant of BCR/ABL-T315I to mediate factor independent growth of 32D cells and strongly reduced their transformation potential in Rat-1 cells, as well as led to the up-regulation of mitogen activated protein kinase (MAPK) pathway.
2.An activating KIT mutation induces crizotinib resistance in ROS1 positive lung cancer.
Dziadziuszko R1, Le AT2, Wrona A1, Jassem J1, Camidge DR2, Varella-Garcia M3, Aisner DL4, Doebele RC5. J Thorac Oncol. 2016 Apr 8. pii: S1556-0864(16)30083-1. doi: 10.1016/j.jtho.2016.04.001. [Epub ahead of print]
INTRODUCTION: Non-small cell lung cancer (NSCLC) patients with ROS1 chromosomal rearrangements benefit from treatment with the ROS1 inhibitor crizotinib. Limited data exist on the spectrum of resistance mechanisms in ROS1+ NSCLC. To delineate mechanisms of acquired resistance, we analyzed tumor samples from biopsies of progressing tumor lesions on crizotinib.
3.A role for FOXO1 in BCR-ABL1-independent tyrosine kinase inhibitor resistance in chronic myeloid leukemia.
Wagle M1, Eiring AM2, Wongchenko M1, Lu S1, Guan Y1, Wang Y1, Lackner M1, Amler L1, Hampton G1, Deininger MW2,3, O'Hare T2,3, Yan Y1. Leukemia. 2016 Mar 8. doi: 10.1038/leu.2016.51. [Epub ahead of print]
Chronic myeloid leukemia (CML) patients who relapse on imatinib due to acquired ABL1 kinase domain mutations are successfully treated with second-generation ABL1-tyrosine kinase inhibitors (ABL-TKIs) such as dasatinib, nilotinib or ponatinib. However, ~40% of relapsed patients have uncharacterized BCR-ABL1 kinase-independent mechanisms of resistance. To identify these mechanisms of resistance and potential treatment options, we generated ABL-TKI-resistant K562 cells through prolonged sequential exposure to imatinib and dasatinib. Dual-resistant K562 cells lacked BCR-ABL1 kinase domain mutations, but acquired other genomic aberrations that were characterized by next-generation sequencing and copy number analyses. Proteomics showed that dual-resistant cells had elevated levels of FOXO1, phospho-ERK and BCL-2, and that dasatinib no longer inhibited substrates of the PI3K/AKT pathway. In contrast to parental cells, resistant cells were sensitive to growth inhibition and apoptosis induced by the class I PI3K inhibitor, GDC-0941 (pictilisib), which also induced FOXO1 nuclear translocation.
