title: A role for FOXO1 in BCR-ABL1-independent tyrosine kinase inhibitor resistance in chronic myeloid leukemia.
abstract: 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. FOXO1 was elevated in a subset of primary specimens from relapsed CML patients lacking BCR-ABL1 kinase domain mutations, and these samples were responsive to GDC-0941 treatment ex vivo. We conclude that elevated FOXO1 contributes to BCR-ABL1 kinase-independent resistance experienced by these CML patients and that PI3K inhibition coupled with BCR-ABL1 inhibition may represent a novel therapeutic approach.
authors.affiliation: Oncology Biomarker Development, Genentech, South San Francisco, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Wagle
authors.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA.
authors.forename: A M
authors.initials: AM
authors.lastname: Eiring
authors.affiliation: Oncology Biomarker Development, Genentech, South San Francisco, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Wongchenko
authors.affiliation: Oncology Biomarker Development, Genentech, South San Francisco, CA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Lu
authors.affiliation: Oncology Biomarker Development, Genentech, South San Francisco, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Guan
authors.affiliation: Oncology Biomarker Development, Genentech, South San Francisco, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Oncology Biomarker Development, Genentech, South San Francisco, CA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Lackner
authors.affiliation: Oncology Biomarker Development, Genentech, South San Francisco, CA, USA.
authors.forename: L
authors.initials: L
authors.lastname: Amler
authors.affiliation: Oncology Biomarker Development, Genentech, South San Francisco, CA, USA.
authors.forename: G
authors.initials: G
authors.lastname: Hampton
authors.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA.|Division of Hematology and Hematologic Malignancies, The University of Utah, Salt Lake City, UT, USA.
authors.forename: M W
authors.initials: MW
authors.lastname: Deininger
authors.affiliation: Huntsman Cancer Institute, The University of Utah, Salt Lake City, UT, USA.|Division of Hematology and Hematologic Malignancies, The University of Utah, Salt Lake City, UT, USA.
authors.forename: T
authors.initials: T
authors.lastname: O'Hare
authors.affiliation: Oncology Biomarker Development, Genentech, South San Francisco, CA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Yan
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000069439:Dasatinib / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004361:Drug Tolerance; D000071161:Forkhead Box Protein O1 / Q000032:analysis / Q000502:physiology*; D016044:Fusion Proteins, bcr-abl / Q000037:antagonists & inhibitors; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology; D007191:Indazoles / Q000494:pharmacology; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D013449:Sulfonamides / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: C532162:2-(1H-indazol-4-yl)-6-(4-methanesulfonylpiperazin-1-ylmethyl)-4-morpholin-4-ylthieno(3,2-d)pyrimidine; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D007191:Indazoles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; D000069439:Dasatinib