Ponatinib Overcomes FGF2-mediated Resistance in CML Patients Without Kinase Domain Mutations

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2014 Jan 11

PMID 24408322

Citations 34

Authors

Elie Traer

Nathalie Javidi-Sharifi

Anupriya Agarwal

Jennifer Dunlap

Isabel English

Jacqueline Martinez

Jeffrey W Tyner

Melissa Wong

Brian J Druker

Affiliations

Soon will be listed here.

Abstract

Development of resistance to kinase inhibitors remains a clinical challenge. Kinase domain mutations are a common mechanism of resistance in chronic myeloid leukemia (CML), yet the mechanism of resistance in the absence of mutations remains unclear. We tested proteins from the bone marrow microenvironment and found that FGF2 promotes resistance to imatinib in vitro. Fibroblast growth factor 2 (FGF2) was uniquely capable of promoting growth in both short- and long-term assays through the FGF receptor 3/RAS/c-RAF/mitogen-activated protein kinase pathway. Resistance could be overcome with ponatinib, a multikinase inhibitor that targets BCR-ABL and FGF receptor. Clinically, we identified CML patients without kinase domain mutations who were resistant to multiple ABL kinase inhibitors and responded to ponatinib treatment. In comparison to CML patients with kinase domain mutations, these patients had increased FGF2 in their bone marrow when analyzed by immunohistochemistry. Moreover, FGF2 in the marrow decreased concurrently with response to ponatinib, further suggesting that FGF2-mediated resistance is interrupted by FGF receptor inhibition. These results illustrate the clinical importance of ligand-induced resistance to kinase inhibitors and support an approach of developing rational inhibitor combinations to circumvent resistance.

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References

Cortes J, Kantarjian H, Shah N, Bixby D, Mauro M, Flinn I . Ponatinib in refractory Philadelphia chromosome-positive leukemias. N Engl J Med. 2012; 367(22):2075-88. PMC: 3777383. DOI: 10.1056/NEJMoa1205127. View

Schmidt T, Kharabi Masouleh B, Loges S, Cauwenberghs S, Fraisl P, Maes C . Loss or inhibition of stromal-derived PlGF prolongs survival of mice with imatinib-resistant Bcr-Abl1(+) leukemia. Cancer Cell. 2011; 19(6):740-53. DOI: 10.1016/j.ccr.2011.05.007. View

Smith B, Levis M, Beran M, Giles F, Kantarjian H, Berg K . Single-agent CEP-701, a novel FLT3 inhibitor, shows biologic and clinical activity in patients with relapsed or refractory acute myeloid leukemia. Blood. 2004; 103(10):3669-76. DOI: 10.1182/blood-2003-11-3775. View

Itkin T, Kaufmann K, Gur-Cohen S, Ludin A, Lapidot T . Fibroblast growth factor signaling promotes physiological bone remodeling and stem cell self-renewal. Curr Opin Hematol. 2013; 20(3):237-44. DOI: 10.1097/MOH.0b013e3283606162. View

Stone R, DeAngelo D, Klimek V, Galinsky I, Estey E, Nimer S . Patients with acute myeloid leukemia and an activating mutation in FLT3 respond to a small-molecule FLT3 tyrosine kinase inhibitor, PKC412. Blood. 2004; 105(1):54-60. DOI: 10.1182/blood-2004-03-0891. View

Paez J, Janne P, Lee J, Tracy S, Greulich H, Gabriel S . EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004; 304(5676):1497-500. DOI: 10.1126/science.1099314. View

OBrien S, Guilhot F, Larson R, Gathmann I, Baccarani M, Cervantes F . Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003; 348(11):994-1004. DOI: 10.1056/NEJMoa022457. View

Kantarjian H, Giles F, Wunderle L, Bhalla K, OBrien S, Wassmann B . Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006; 354(24):2542-51. DOI: 10.1056/NEJMoa055104. View

Singh D, Chan J, Zoppoli P, Niola F, Sullivan R, Castano A . Transforming fusions of FGFR and TACC genes in human glioblastoma. Science. 2012; 337(6099):1231-5. PMC: 3677224. DOI: 10.1126/science.1220834. View

10.

Richelda R, Ronchetti D, Baldini L, Cro L, Viggiano L, Marzella R . A novel chromosomal translocation t(4; 14)(p16.3; q32) in multiple myeloma involves the fibroblast growth-factor receptor 3 gene. Blood. 1997; 90(10):4062-70. View

11.

Gorre M, Mohammed M, Ellwood K, Hsu N, Paquette R, Rao P . Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification. Science. 2001; 293(5531):876-80. DOI: 10.1126/science.1062538. View

12.

Yadav V, Zhang X, Liu J, Estrem S, Li S, Gong X . Reactivation of mitogen-activated protein kinase (MAPK) pathway by FGF receptor 3 (FGFR3)/Ras mediates resistance to vemurafenib in human B-RAF V600E mutant melanoma. J Biol Chem. 2012; 287(33):28087-98. PMC: 3431627. DOI: 10.1074/jbc.M112.377218. View

13.

Zhao M, Ross J, Itkin T, Perry J, Venkatraman A, Haug J . FGF signaling facilitates postinjury recovery of mouse hematopoietic system. Blood. 2012; 120(9):1831-42. PMC: 3433089. DOI: 10.1182/blood-2011-11-393991. View

14.

Flaherty K, Puzanov I, Kim K, Ribas A, McArthur G, Sosman J . Inhibition of mutated, activated BRAF in metastatic melanoma. N Engl J Med. 2010; 363(9):809-19. PMC: 3724529. DOI: 10.1056/NEJMoa1002011. View

15.

Druker B, Guilhot F, OBrien S, Gathmann I, Kantarjian H, Gattermann N . Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006; 355(23):2408-17. DOI: 10.1056/NEJMoa062867. View

16.

Ware K, Hinz T, Kleczko E, Singleton K, Marek L, Helfrich B . A mechanism of resistance to gefitinib mediated by cellular reprogramming and the acquisition of an FGF2-FGFR1 autocrine growth loop. Oncogenesis. 2013; 2:e39. PMC: 3641357. DOI: 10.1038/oncsis.2013.4. View

17.

Straussman R, Morikawa T, Shee K, Barzily-Rokni M, Qian Z, Du J . Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature. 2012; 487(7408):500-4. PMC: 3711467. DOI: 10.1038/nature11183. View

18.

Degnin C, Laederich M, Horton W . Ligand activation leads to regulated intramembrane proteolysis of fibroblast growth factor receptor 3. Mol Biol Cell. 2011; 22(20):3861-73. PMC: 3192865. DOI: 10.1091/mbc.E11-01-0080. View

19.

Ernst T, La Rosee P, Muller M, Hochhaus A . BCR-ABL mutations in chronic myeloid leukemia. Hematol Oncol Clin North Am. 2011; 25(5):997-1008, v-vi. DOI: 10.1016/j.hoc.2011.09.005. View

20.

OHare T, Shakespeare W, Zhu X, Eide C, Rivera V, Wang F . AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009; 16(5):401-12. PMC: 2804470. DOI: 10.1016/j.ccr.2009.09.028. View