p53 and autophagy contribute to dasatinib resistance in primary CLL lymphocytes.
B-cell chronic lymphocytic leukemia (CLL) is the most common leukemia in adults and there is no cure for the disease. Although dasatinib is cytotoxic to primary CLL lymphocytes in vitro, the drug has been shown to be active in a small percent of CLL patients. Our previous results suggest that dasatinib targets del17 CLL lymphocytes which are the CLL patients with the worst prognosis. Here we present mechanistic evidence that dasatinib induces endoplasmic reticulum stress and autophagy in CLL lymphocytes. Furthermore we provide evidence suggesting that autophagy mediates resistance to the drugs, process that is modulated by p53.
Amrein
Lilian
L
Lady Davis Institute for Medical Research, Cancer Segal Center, Sir M.B. Davis Jewish General Hospital, QC, Canada.
Soulières
Denis
D
Johnston
James B
JB
Aloyz
Raquel
R
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001343:Autophagy; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use*; D013844:Thiazoles / Q000627:therapeutic use*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
D000970:Antineoplastic Agents; D011743:Pyrimidines; D013844:Thiazoles; D016159:Tumor Suppressor Protein p53; D000069439:Dasatinib