BCR-ABL mutants spread resistance to non-mutated cells through a paracrine mechanism.
Patients with chronic myeloid leukemia who become resistant to the Abl kinase inhibitor imatinib can be treated with dasatinib. This sequential treatment can lead to BCR-ABL mutations conferring broad resistance to kinase inhibitors. To model the evolution of resistance, we exposed the mouse DA1-3b BCR-ABL(+) leukemic cell line to imatinib for several months, and obtained resistant cells carrying the E255K mutation. We then exposed these cells to dasatinib, and obtained dasatinib-resistant cells with composite E255K+T315I mutations. Subcloning isolated a minor clone also carrying V299L. In co-culture, mutated cells were able to spread resistance to non-mutated cells through overexpression of interleukin 3, activation of MEK/ERK and JAK2/STAT5 pathways, and downregulation of Bim. Even the presence of less than 10% of mutated cells was sufficient to protect non-mutated cells. Blocking JAK2 and MEK1/2 inhibited the protective effect of co-culture. Mutated cells were also sensitive to JAK2 inhibition, but blocking MEK1/2 alone, or in association with kinase inhibitors, had little effect. These data indicate that sequential Abl kinase inhibitor therapy can generate sub-populations of mutated cells, which may coexist with non-mutated cells and protect them through a paracrine mechanism. Targeting JAK2 could eliminate both populations.
Liu
J
J
INSERM, Unité 837, Equipe 3, Institut de Recherche sur le Cancer de Lille, Lille, France.
Joha
S
S
Idziorek
T
T
Corm
S
S
Hetuin
D
D
Philippe
N
N
Preudhomme
C
C
Quesnel
B
B
D000818:Animals; D001549:Benzamides; D002460:Cell Line; D018920:Coculture Techniques; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases; D016044:Fusion Proteins, bcr-abl / Q000235:genetics*; D000068877:Imatinib Mesylate; D007377:Interleukin-3; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D020929:Mitogen-Activated Protein Kinase Kinases; D023421:Models, Animal; D020125:Mutation, Missense; D019899:Paracrine Communication; D010879:Piperazines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D050799:STAT5 Transcription Factor; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology
D001549:Benzamides; D007377:Interleukin-3; D010879:Piperazines; D011743:Pyrimidines; D050799:STAT5 Transcription Factor; D013844:Thiazoles; D000068877:Imatinib Mesylate; D016044:Fusion Proteins, bcr-abl; C507926:Jak2 protein, mouse; D053614:Janus Kinase 2; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D000069439:Dasatinib