Sequential ABL kinase inhibitor therapy selects for compound drug-resistant BCR-ABL mutations with altered oncogenic potency

Abstract

Molecularly targeted kinase inhibitor cancer therapies are currently administered sequentially rather than simultaneously. We addressed the potential long-term impact of this strategy in patients with chronic myelogenous leukemia (CML), which is driven by the fusion oncogene BCR-ABL. Analysis of BCR-ABL genotypes in CML patients who relapsed after sequential treatment with the ABL inhibitors imatinib and dasatinib revealed evolving resistant BCR-ABL kinase domain mutations in all cases. Twelve patients relapsed with the pan-resistant T315I mutation, whereas 6 patients developed novel BCR-ABL mutations predicted to retain sensitivity to imatinib based on in vitro studies. Three of these patients were retreated with imatinib (or the chemically related compound nilotinib) and responded; however, selection for compound mutants (2 or 3 BCR-ABL mutations in the same molecule) can substantially limit the potential effectiveness of retreating patients with inhibitors that have previously failed. Furthermore, drug-resistant mutations, when compounded, can increase oncogenic potency relative to the component mutants in transformation assays. The Aurora kinase inhibitor VX-680, currently under clinical evaluation based on its activity against the T315I mutation, is also effective against the other commonly detected dasatinib-resistant mutation in our analysis, V299L. Our findings demonstrate the potential hazards of sequential kinase inhibitor therapy and suggest a role for a combination of ABL kinase inhibitors, perhaps including VX-680, to prevent the outgrowth of cells harboring drug-resistant BCR-ABL mutations.

BCR-ABL mutants spread resistance to non-mutated cells through a paracrine mechanism

“…It too binds to mutated BCR-ABL and is now routinely used in patients who become resistant to imatinib. [1][2][3] Dasatinib treatment can lead to new BCR-ABL mutations. Some, like T315I, confer resistance to both imatinib and dasatinib, and others, like V299L, confer resistance to dasatinib only.…”

HPLC–MS method for the simultaneous quantification of the antileukemia drugs imatinib, dasatinib and nilotinib in human peripheral blood mononuclear cell (PBMC)

“…In order to manage primary or acquired resistance to imatinib, clinical studies using dasatinib or nilotinib as second line therapy or combination of therapies with different TKIs, in sequential or simultaneous administration, are currently under evaluation [21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39]. Sub-inhibitory intracellular drug concentrations, probably, and sequential treatment with multiple tyrosine kinase inhibitors promote the selection of BCR-ABL kinase domain mutations in CML patients [51][52]. Poor penetration of drugs into leukocytes or PBMC, inadequate treatment adherence, and variability in drug PK may also contribute to the occurrence of sub-therapeutic drug level.…”

Tyrosine Kinase Inhibitor Therapy for Chronic Myeloid Leukemia: Approach to Patients with Treatment-Naive or Refractory Chronic-Phase Disease

“…Notable exceptions are the highly resistant T315I mutation, which fails to respond objectively to dasatinib, and the moderately resistant F317L mutation, 37 which is frequently associated with hematologic response, rarely with cytogenetic response, and occasionally with secondary resistance to dasatinib. 38 Other imatinib-resistant mutations with moderate relative resistance to dasatinib include G250E and E255V/K (although many reports of achievement of CCyR have been reported in patients with these mutations) and V299L. 37 In a randomized phase 3 study in imatinib-resistant or -intolerant CP-CML, of 164 patients randomized to receive dasatinib 100 mg once daily, 50% of patients achieved CCyR.…”