Persistent Cdk2 inactivation drives growth arrest of BCR-ABL-expressing cells in response to dual inhibitor of SRC and ABL kinases SKI606.
Complementary inhibition of tyrosine and SRC kinases implement dual SRC/ABL inhibitor effects in chronic myeloid leukemia (CML). Here, we show that one such inhibitor, SKI-606, induces persistent Cdk2 inactivation leading to growth arrest of BCR-ABL-expressing cells either IM-sensitive or driven to IM-resistance by other events than gene overexpression and point mutations. Inhibition of Akt serine/threonine kinase, a phosphatidylinositol 3 kinase (PI-3k) target that integrates p210 TK signaling with membrane-associated SRC kinases, is a central component of restored expression and subcellular redistribution of Cdk2 regulatory signals (p21 and p27 and Cdc25A phosphatase) in response to SKI-606. The putative roles of growth factor (namely IL-3) autocrine loop in BCR-ABL-expressing progenitor progression towards a drug-resistant phenotype are discussed.
Mancini
Manuela
M
Istituto di Ematologia e Oncologia Medica "Lorenzo e Ariosto Seràgnoli", University of Bologna-Medical School, Via Massarenti 9, 40138-Bologna, Italy. mancini_manu@yahoo.com
Brusa
Gianluca
G
Zuffa
Elisa
E
Corrado
Patrizia
P
Martinelli
Giovanni
G
Grafone
Tiziana
T
Barbieri
Enza
E
Santucci
Maria Alessandra
MA
D000814:Aniline Compounds / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D007377:Interleukin-3 / Q000378:metabolism; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000378:metabolism / Q000473:pathology*; D009570:Nitriles / Q000494:pharmacology*; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D016315:Proto-Oncogene Proteins c-abl / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D020687:cdc25 Phosphatases / Q000378:metabolism; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
D000814:Aniline Compounds; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D004791:Enzyme Inhibitors; D007377:Interleukin-3; D009570:Nitriles; D011804:Quinolines; D050760:Cyclin-Dependent Kinase Inhibitor p27; C471992:bosutinib; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl; D016315:Proto-Oncogene Proteins c-abl; D019061:src-Family Kinases; D051057:Proto-Oncogene Proteins c-akt; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; C517004:CDC25A protein, human; D020687:cdc25 Phosphatases