Biological Pathway: Reactome:R-HSA-9674415

Drug resistance of PDGFR mutants related metabolites

find 4 related metabolites which is associated with the biological pathway Drug resistance of PDGFR mutants

this pathway object is a organism specific pathway, which is related to taxonomy Homo sapiens (human).

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).