FGF2 induces imatinib resistance in CML cells via reactivation of FGFR3–RAS–MAPK signaling.

  • Major finding: FGF2 induces imatinib resistance in CML cells via reactivation of FGFR3–RAS–MAPK signaling.

  • Clinical relevance: Patients with increased marrow FGF2 who lack BCR–ABL kinase domain mutations respond to ponatinib.

  • Impact: Combined inhibition of ligand-mediated survival and kinase activity may overcome resistance.

Inhibition of BCR–ABL tyrosine kinase activity has had clear clinical success in patients with chronic myeloid leukemia (CML) but often leads to resistance due to acquired mutations within the BCR–ABL kinase domain. Interestingly, resistance to BCR–ABL inhibitors such as imatinib has also been observed in a subset of patients with CML that lack kinase domain mutations, prompting Traer and colleagues to investigate the role of the bone marrow microenvironment in promoting CML cell survival and driving imatinib resistance. Of the bone marrow proteins tested, exogenous fibroblast growth factor 2 (FGF2) was found to best promote imatinib resistance in both short-term and long-term CML cell-growth assays. Mechanistically, the majority of long-term resistant cultures were dependent on FGF2 for survival via signaling through the FGF receptor 3 (FGFR3)–RAS–c-RAF–MAPK pathway. Combinatorial treatment with imatinib and an FGFR kinase inhibitor resulted in synergistic killing in the majority of FGF2-driven resistant cultures, suggesting that simultaneous targeting of these pathways may have a better clinical outcome. In support of this idea, ponatinib, a BCR–ABL kinase inhibitor that also exhibits activity against FGFR, induced a robust antiproliferative response in FGF2-dependent long-term cultures that remained resistant to BCR–ABL inhibition alone. Clinically, FGF2 expression was elevated in stromal and hematopoietic progenitor cells in bone marrow biopsies from ponatinib-sensitive patients without kinase domain mutations compared with patients with kinase domain mutations. Furthermore, response to ponatinib treatment was associated with a concomitant reduction in FGF2 levels in bone marrow cells. Together, these results highlight how ligand-mediated signaling pathways can drive resistance to kinase inhibitors and provide a rationale for combination therapy as a means to achieve sustained clinical response in patients with CML.

Traer E, Javidi-Sharifi N, Agarwal A, Dunlap J, English I, Martinez J, et al. Ponatinib overcomes FGF2-mediated resistance in CML patients without kinase domain mutations. Blood 2014 Jan 9 [Epub ahead of print].

©2014 American Association for Cancer Research.
2014