DDR2 (discoidin death receptor 2) is a
member of the DDR family of receptor
tyrosine kinases that are stimulated by
collagen rather than peptide growth
factors (Figure 1). Downstream signaling in cancer cells is poorly understood but may be via
SRC and STAT signaling pathways. Similar
to integrin receptors, DDR2 may play a
role in modulating cellular interactions with the extracellular matrix.
DDR2 mutations have been found at low
frequency in a number of cancers, including renal cell carcinoma, glioblastoma multiforme,
endometrial cancer, colorectal cancer (COSMIC).
The highest reported frequency is in squamous cell carcinoma of the lung (Hammerman
et al. 2011).
Figure 1. Schematic of DDR2 signaling pathway. Binding of collagen to DDR2 results in
activation of downstream signaling pathways.
The letter "K" within the schema denotes the tyrosine kinase
Suggested Citation: Paik, P. 2015. DDR2. My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/ddr2/?tab=0
(Updated December 7).
Last Updated: December 7, 2015
DDR2 in NSCLC
DDR2 mutations have been found in
2.5–3.8% of squamous cell carcinomas of the lung and in 4% of lung tumors with
adenocarcinoma histology (COSMIC; Hammerman
et al. 2011). No hotspots have been identified, with mutations spanning both
the kinase and discoidin domains (the latter of which forms part of the extracellular region
that binds to collagen; Ichikawa et al. 2007). Neither
overexpression of DDR2 nor copy number alterations of the DDR2 locus (1q23) has
While there are limited data on the clinical characteristics of patients harboring
DDR2 mutations, no significant
association with sex, age, or smoking status has been found.
Suggested Citation: Paik, P. 2015. DDR2 in NSCLC. My Cancer Genome
(Updated June 18).
Last Updated: June 18, 2015
DDR2 c.2304T>A (S768R) Mutation in Squamous Cell Carcinoma of the Lung
The S768R mutation results in an amino acid substitution at position 768 in
DDR2, from serine (S) to an arginine (R). This mutation
occurs in the kinase domain (Figure 1).
Mutant DDR2 proteins are transforming in
vitro. Cell lines harboring DDR2 mutations appear to be dependent upon mutant
kinase activity for growth and survival.
a Dasatinib had been shown to be an inhibitor of DDR2 in an in vitro screen
al. 2008), but dasatinib also inhibits multiple other kinases. Squamous cell lung cancer cells expressing the
I638F and L239R mutant receptors are
sensitive to treatment with dasatinib (IC50 for cell death, 139–140nM). In addition,
mouse xenografts derived from these cell lines regressed following treatment with dasatinib
et al. 2011).
A DDR2 S768R mutation was found in the
single squamous cell carcinoma of the lung that responded to treatment in an early-phase
clinical trial of dasatinib + erlotinib. An overlapping EGFR mutation was not
present (Hammerman et al. 2011). In a case report, a patient
with chronic myelogenous leukemia and squamous cell carcinoma of the lung harboring a DDR2
S768R mutation responded to dasatinib therapy (Pitini et al.
2013). A phase II clinical trial of dasatinib in patients with advanced cancer
harboring a DDR2 mutation is ongoing.
While relatively uncommon, DDR2 mutations
identify a subgroup of patients in whom treatment with an existing, well-characterized drug
may prove beneficial.
Figure 1. Schematic of DDR2 S768R mutation. Functional domains of DDR2 are
Suggested Citation: Paik, P. 2014. DDR2 c.2304T>A (S768R) Mutation in Squamous Cell Carcinoma of the Lung.
My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/ddr2/78/
(Updated April 8).
Last Updated: April 8, 2014
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