PDGFRA encodes a cell surface tyrosine
kinase receptor for members of the platelet-derived growth factor family. These
growth factors are mitogens for cells of mesenchymal origin. The identity of
the growth factor bound to a receptor monomer determines whether the functional
receptor is a homodimer or a heterodimer, composed of both platelet-derived
growth factor receptor alpha and beta polypeptides. Activation of PDGFRA kinase
activity initiates intracellular signaling through the MAPK, PI 3-K and PKCγ pathways.
Somatic PDGFRA mutations have been found
in tumors of small intestine (about 50% of cases), stomach and soft tissue.
Two-thirds of these mutations are “substitution missense”, for which a mutation
hot spot exists, corresponding to amino acid 842.
Gastrointestinal stromal tumors (GISTs)
are rare neoplasms of mesenchymal origin arising in the gastrointestinal tract.
These tumors are characterized by activating mutations of either receptor
tyrosine kinase KIT or PDGFRA, which are found in 85% of cases.
Fusion genes involving PDGFRA and various
other genes (FIP1L1, CDK5RAP2, STRN, KIF5B, ETV6, BCR is the cause of diseases
accompanied by eosinophilia (see below):
del(4)(q12q12) FIP1L1-PDGFRA ●
ins(9;4)(q33;q12q25) CDK5RAP2-PDGFRA ●
t(2;4)(p22;q12) STRN-PDGFRA ●
MPD with eosinophilia
t(4;10)(q12;p11) KIF5B-PDGFRA ●
MPS with hypereosinophilia
t(4;12)(q12;p13) ETV6-PDGFRA ●
MPD with hypereosinophilia
t(4;22)(q12;q11.2) BCR-PDGFRA ●
MPD and atypical CML
The most investigated of these fusion genes isFIP1L1-PDGFRA (see, among others, Fukushima et al. 2009).
The introduction of imatinib mesylate,
which targets the kinases presenting with PDGFRA or KIT alterations, has
dramatically changed the management of GISTs, which were resistant to
conventional cytotoxic chemotherapy, both in advanced and localized phases.
However, although the majority of GISTs show an initial clinical response to
imatinib, the development of resistance to this tyrosine kinase inhibitor as
well as to the alternative kinase inhibitor sunitinib is problematic
(Downs-Kelly & Rubin, 2011).
Rare cases of mutant FIP1L1-PDGFRA that are resistant
to imatinib mesylate (eg, T674I, D842V) have been reported. In vitro, the
T674I, but not the D842V, mutant was shown to be sensitive to other kinase
inhibitors, including nilotinib, sorafenib, and PKC412 . Also, there are
reported instances of interferon alfa–induced complete clinical remissions in
FIP1L1-PDGFRA–positive clonal eosinophilia (Tefferi et al. 2010)
References (open access):
Gastrointestinal stromal tumors: molecular mechanisms and targeted
therapies. Downs-Kelly E, Rubin BP. Patholog Res Int. 2011 Apr 14;2011:708596.
FIP1L1-PDGFRalpha imposes eosinophil lineage commitment on hematopoietic
stem/progenitor cells. Fukushima K, Matsumura I, Ezoe S, Tokunaga M, Yasumi M,
Satoh Y, Shibayama H, Tanaka H, Iwama A, Kanakura Y. J Biol Chem. 2009 Mar