Drug resistance of PDGFR mutants

Stable Identifier
Homo sapiens
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PDGFRA is mutated in ~10% of gastrointestinal stromal tumors in a mutually exclusive manner with KIT mtutations. In contrast to KIT, PDGFRA GIST mutations occur more frequently in the activation domain, rather than the juxtamembrane domain. In addition to GIST, PDGFRA is subject to missense or small in-frame deletion mutations in haematological cancers and melanoma. In contrast, missense mutations in PDGFRB are rare (Heinrich et al, 2003; Corless et al, 2005; reviewed in Corless et al, 2011). Both PDGFRA and PDGFRB are also subject to oncogenic translocation events leading to the expression of fusion proteins (Cools et al, 2003; Simon et al, 2008; Salemi et al, 2009; Ohashi et al, 2010; reviewed in Appiah-Kubi et al, 2017).
Imatinib is a type II TKIs that is approved as first-line treatment of KIT- and PDGFR-driven tumors; however secondary mutations frequently contribute to the development of imatinib resistance. These secondary mutations further shift the equilibrium of the receptor toward the activated state, making imatinib and even approved second-line type II TKIs less effective. In consequence, considerable effort is devoted to discovery of type II and, in particular, type I TKIs that are active against highly activated PDGFR alleles (Smith et al, 2019; Lierman et al, 2019; reviewed in Roskoski, 2018; Klug et al, 2018).
Literature References
PubMed ID Title Journal Year
29408302 The role of small molecule platelet-derived growth factor receptor (PDGFR) inhibitors in the treatment of neoplastic disorders

Roskoski, R

Pharmacol. Res. 2018
31723821 FIP1L1-PDGFRα p.T674I-D842L: A Novel and Ponatinib Resistant Compound Mutation in FIP1L1-PDGFRα Positive Leukemia

Smits, S, Appleby, N, Conneally, E, Vandenberghe, P, Michaux, L, Lierman, E

Hemasphere 2019
15221957 Different inhibitory effect of imatinib on phosphorylation of mitogen-activated protein kinase and Akt and on proliferation in cells expressing different types of mutant platelet-derived growth factor receptor-alpha

Kitamura, Y, Shinomura, Y, Isozaki, K, Nishida, T, Kinoshita, K, Ohashi, A, Hirota, S

Int. J. Cancer 2004
12522257 PDGFRA activating mutations in gastrointestinal stromal tumors

Corless, CL, Heinrich, MC, Singer, S, Griffith, DJ, Town, A, Haley, A, Duensing, A, McGreevey, L, Fletcher, JA, Demetri, GD, Joseph, N, Chen, CJ, Fletcher, CD

Science 2003
18234315 Primary resistance to imatinib in Fip1-like 1-platelet-derived growth factor receptor alpha-positive eosinophilic leukemia

Yousefi, S, Simon, D, Salemi, S, Simon, HU

J. Allergy Clin. Immunol. 2008
19210352 A novel FIP1L1-PDGFRA mutant destabilizing the inactive conformation of the kinase domain in chronic eosinophilic leukemia/hypereosinophilic syndrome

Scapozza, L, Simon, D, Salemi, S, Moretti, L, Simon, HU, Yousefi, S, Schmid, I

Allergy 2009
28010895 Platelet-derived growth factor receptors (PDGFRs) fusion genes involvement in hematological malignancies

Yao, X, Chen, Y, Wu, M, Qian, H, Wang, Y, Wu, Y, Appiah-Kubi, K, Lan, T

Crit. Rev. Oncol. Hematol. 2017
29964125 Structural and clinical consequences of activation loop mutations in class III receptor tyrosine kinases

Heinrich, MC, Kent, JD, Klug, LR

Pharmacol. Ther. 2018
15928335 PDGFRA mutations in gastrointestinal stromal tumors: frequency, spectrum and in vitro sensitivity to imatinib

Shiraga, S, McGreevey, L, Schroeder, A, Corless, CL, Heinrich, MC, Harrell, P, Morich, J, Bainbridge, T, Town, A, Griffith, D

J. Clin. Oncol. 2005
31085175 Ripretinib (DCC-2618) Is a Switch Control Kinase Inhibitor of a Broad Spectrum of Oncogenic and Drug-Resistant KIT and PDGFRA Variants

Hood, MM, Gupta, A, Su, Y, Ensinger, CL, Caldwell, TM, Bulfer, SL, Heinrich, MC, Al-Ani, G, Ahn, YM, Patt, WC, Janku, F, Turner, BA, Ruiz-Soto, R, Leary, CB, Abdul Razak, AR, Yates, K, Town, A, Rosen, O, Wise, SC, Vogeti, L, Telikepalli, H, Rutkoski, TJ, Vogeti, S, Smith, BD, Flynn, DL, Chun, L, Lu, WP, Kaufman, MD, McKinley, A

Cancer Cell 2019
Name Identifier Synonyms
cancer DOID:162 malignant tumor, malignant neoplasm, primary cancer
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