• What is DDR2?
  • DDR2 in Lung Cancer
  • DDR2 c.2304T>A (S768R)
  • Clinical Trials

DDR2

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).

ddr2.png

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 domain.

Related Pathways

Contributors: Paul K. Paik, M.D.

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 (COSMICHammerman 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 been reported.

 

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.​​​

 

Contributors: Paul K. Paik, M.D.

Suggested Citation: Paik, P. 2015. DDR2 in NSCLC. My Cancer Genome https://www.padiracinnovation.org/content/disease/lung-cancer/ddr2/ (Updated June 18).

Last Updated: June 18, 2015

DDR2 c.2304T>A (S768R) Mutation in Squamous Cell Carcinoma of the Lung

Properties
Location of mutation Kinase domain (exon 18)
Frequency of DDR2 mutations in SCC of the lung 2.5–3.8% (COSMIC; Hammerman et al. 2011)
Frequency of S768R mutations in DDR2-mutated SCC of the lung Two cases reported (Hammerman et al. 2011; Pitini et al. 2013)
Implications for Targeted Therapeutics
Response to dasatinib Unknown at this timea

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 (Day et 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 (Hammerman 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.

ddr2-s768r.png

Figure 1.
Schematic of DDR2 S768R mutation. Functional domains of DDR2 are depicted.

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Contributors: Paul K. Paik, M.D.

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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