RET Fusions

RET (“rearranged during transfection”) is a single-pass transmembrane receptor tyrosine kinase required for normal cellular differentiation, maturation and maintenance. Under normal physiological conditions, RET signaling is activated by binding of a group of soluble proteins of the glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs).1,2 In some heritable and sporadic tumors, however, RET signaling can be constitutively activated in a ligand-independent fashion due to gain of function RET point mutations or genomic rearrangements resulting in oncogenic fusion proteins. This, in turn, results in the activation of the various signaling cascades that lie downstream, including RAS-MAPK, PI3K-AKT, and phospholipase Cγ (PLCγ) pathways. This drives prolonged cell survival and increased proliferation.1, 3, 4. RET fusions have been observed in papillary thyroid cancer, lung adenocarcinoma and colorectal cancer, among other solid tumors. Recently, the RET fusion gene was identified as a new druggable driver gene, sparking an increased interest in identifying RET as a therapeutic target.1, 3

RET Fusion Clinical Prevalence in Lung Cancer

A recent study5 reported 13 out of 936 patients with RET fusion (11 out of 633 patients with adenocarcinoma, 2 out of 24 patients with adenosquamous carcinoma). Of the 13 patients with gene fusions, nine were found to have KIF5B-RET, three had CCDC6-RET and one had NCOA4-RET, a recently discovered gene fusion. Patients with a RET gene fusion manifested a poor differentiation of tumor cells (63.6%; p=0.029 for RET vs. ALK, p=0.007 for RET vs. EGFR), with a tendency to be younger (≤60 years; 72.7%), never-smokers (81.8%), with solid subtype (63.6%), smaller tumor (≤3 cm), and N2 disease (54.4%). The median relapse-free survival was 20.9 months5.

In 2014, Tsuta et al. investigated RET fusions across a sample of 874 patients (1620 adenocarcinomas (ADCs), 203 squamous cell carcinomas (SCCs), 8 large cell carcinomas, and 43 sarcomatoid carcinomas (SACs). In all, 22 cases (1.2%) showed RET rearrangements; all cases were ADC histology. Of the 22 patients, 19 possessed KIF5B–RET gene fusions, whereas three possessed CCDC6–RET gene fusions. The RET-rearranged tumors were significantly more common in younger patients (p=0.038) and tended to occur in patients with no history of smoking (P=0.051),6 thus reinforcing the findings mentioned above.

The clinical prevalence of RET fusions in NSCLC is listed below (adapted from Kohno, 20133).

Table may scroll right >>

Institution No. of cases examined No. of RET fusion (+) cases RET fusion detection rate (%) Fusion partners (number of observations)
NSCLC/lung adenocarcinoma
National Cancer Center, Japan 704/433 7/7 1.0/1.6 KIF5B (7)
Japan Foundation for Cancer Research, Japan 1482/1119 13/13 0.9/1.2 KIF5B (12)
CCDC6 (1)
Foundation Med, USA 643/561 12/12 1.8/2.1 KIF5B (12)
Seoul National University, Korea 21/21 3/3 14/14 KIF5B (3)
Chinese Academy of Sciences, China 202/202 2/2 1.0/1.0 CCDC6 (2)
Nagoya City University, Japan 371/270 3/3 0.8/1.1 KIF5B (3)
Memorial Sloan Kettering Cancer Center, USA 69/69 1/1 1.4/1.4 KIF5B (1)
Fudan University Shanghai Cancer Center, China 936/633 13/11 1.4/1.7 KIF5B (9)
CCDC6 (3)
NCOA4 (1)
Tongji University School of Medicine, China 392/231 6/4 1.5/1.7 KIF5B (6)
Korea Research Institute of Bioscience and Biotechnology, Korea 6/6 1/1 17/17 CCDC6 (1)
Memorial Sloan-Kettering Cancer Center, USA 31/31 5/5

 

16/16

 

KIF5B (2)
TRIM33 (1)
Unknown (2)
Total 4857/3576 66/62 1.4/1.8 KIF5B (55)
CCDC6 (7)
NCOA4 (1)
TRIM33 (1)

RET Fusion Clinical Prevalence in Other Cancer Histologies

In addition to lung cancer, RET fusions have been observed in other cancer histologies, as summarized below.

Tumor histology RET fusion detection rate (%) Fusion partners
Papillary thyroid cancer (PTC) 6% 7,8 AKAP13, FKBP15, HOOK3, PCM1, PRKAR1A, SPECC1L, TBL1XR1, TRIM24, TRIM27, CCDC6, ERC1, KIF5B, NCOA4, GOLGA5, KTN1, RFG9
Colorectal cancer (CRC) 0.2-0.4% 7,9 CCDC6, NCOA4
Breast cancer (BC) 0.1% 7 ERC1
Spitz Tumors 3% 10 GOLGA5, KIF5B
Chronic myelomonocytic leukemia (CMML) <1% 11 BCR, FGFR1OP

RET Gene Fusions in Cancer

(adapted from Lee, 201512)

RET-fusion proteins in thryoid, lung, and other types of cancers
RET-fusion proteins in thryoid, lung, and other types of cancers

 

References

  1. Nakagawara A. Trk receptor tyrosine kinases: a bridge between cancer and neural development. Cancer Lett. 2001; 169(2):107-114.
  1. Thiele CJ, Li Z, McKee AE. On Trk–the TrkB signal transduction pathway is an increasingly important target in cancer biology. Clin Cancer Res. 2009; 15(19):5962-5967.
  1. Shaw AT, Hsu PP, Awad MM, Engelman JA. Tyrosine kinase gene rearrangements in epithelial malignancies. Nat Rev Cancer. 2013; 13(11):772-787.
  1. Greco A, Miranda C, Pierotti MA. Rearrangements of NTRK1 gene in papillary thyroid carcinoma. Mol Cell Endocrinol. 2010; 321(1):44-49.
  1. Kaplan DR, Miller FD. Neurotrophin signal transduction in the nervous system. Curr Opin Neurobiol. 2000; 10(3): 381-391.
  1. Sartore-Bianchi A, Ardinia E, Bosotti R, et al. Sensitivity to Entrectinib Associated With a Novel LMNA-NTRK1 Gene Fusion in Metastatic Colorectal Cancer. J Natl Cancer Inst. 2016; 108(1): djv306
  1. Vaishnavi A, Capelletti M, Le AT, et al. Oncogenic and drug sensitive NTRK1 rearrangements in lung cancer. Nat Med. 2013;19(11):1469–1472.
  1. Farago AF, Le LP, Zheng Z, et al. Durable Clinical Response to Entrectinib in NTRK1 -Rearranged Non-Small Cell Lung Cancer. J Thorac Oncol. 2015;10(12):1670-1674.
  1. Prasad ML, Vyas M, Horne MJ, et al. NTRK fusion oncogenes in pediatric papillary thyroid carcinoma in northeast United States. Cancer. 2016 Jan 19. doi: 10.1002/cncr.29887. [Epub ahead of print]
  1. Park DY, Choi C, Shin E, et al. NTRK1 fusions for the therapeutic intervention of Korean patients with colon cancer. Oncotarget. 2015. doi: 10.18632/oncotarget.6724. [Epub ahead of print]
  1. Wiesner T, He J, Yelensky R, et al. Kinase fusions are frequent in Spitz tumours and spitzoid melanomas. Nat Commun. 2014; 5:3116. doi: 10.1038/ncomms4116.
  1. Squinto SP, Stitt TN, Aldrich TH, et al. TrkB encodes a functional receptor for brain-derived neurotrophic factor and neurotrophin-3 but not nerve growth factor. Cell. 1991; 65(5):885-893. [Need to order]
  1. Klein R, Nanduri V, Jing SA, et al. The trkB tyrosine protein kinase is a receptor for brain-derived neurotrophic factor and neurotrophin-3. Cell. 1991; 66(2): 395-403.
  1. Douma S, Van Laar T, Zevenhoven J, Meuwissen R, Van Garderen E, Peeper DS. Suppression of anoikis and induction of metastasis by the neurotrophic receptor TrkB. Nature. 2004;430(7003):1034-1039.
  1. de Farias CB, Heinen TE, dos Santos RP, Abujamra AL, Schwartsmann G, Roesler R. BDNF/TrkB signaling protects HT-29 human colon cancer cells from EGFR inhibition. Biochem Biophys Res Commun. 2012; 425(2): 328-332.
  1. Jones DT, Hutter B, Jäger N, et al; International Cancer Genome Consortium PedBrain Tumor Project. Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat Genet. 2013; 45(8):927-932.
  1. Tognon, C. et al. Expression of the ETV6-NTRK3 gene fusion as a primary event in human secretory breast carcinoma. Cancer Cell. 2002; 2, 367–376.
  1. Knezevich SR, McFadden DE, Tao W, Lim JF, Sorensen PH. A novel ETV6-NTRK3 gene fusion in congenital fibrosarcoma. Nat Genet. 1998; 18(2):184-187.
  1. Jin W, Yun C, Hobbie A, Martin MJ, Sorensen PH, Kim SJ. Cellular transformation and activation of the phosphoinositide-3-kinase-Akt cascade by the ETV6-NTRK3 chimeric tyrosine kinase requires c-Src. Cancer Res. 2007; 67(7):3192-3200.
  1. Tognon C, Garnett M, Kenward E, Kay R, Morrison K, Sorensen PH. The chimeric protein tyrosine kinase ETV6-NTRK3 requires both Ras-Erk1/2 and PI3-kinase-Akt signaling for fibroblast transformation. Cancer Res. 2001; 61(24):8909-8916.
  1. Stransky N, Cerami E, Schalm S, Kim JL, Lengauer C. The landscape of kinase fusions in cancer. Nat Commun. 2014;5: 4846. doi: 10.1038/ncomms5846.
  1. Doebele RC, Davis LE, Vaishnavi A, et al. An Oncogenic NTRK Fusion in a Patient with Soft-Tissue Sarcoma with Response to the Tropomyosin-Related Kinase Inhibitor LOXO-101. Cancer Discov. 2015; 5(10):1049-1057.

The Rx/Dx Advantage

Decoding the underlying causes of cancer is an evolving field, with much at stake from all sides. Learn more about Ignyta’s Rx/Dx Advantage and how we’re working with healthcare providers to change cancer treatment and care.

Ignyta Scientific Presentations

A database of Ignyta’s clinical, scientific, and technical data on precision therapeutic candidates and diagnostic tests. See Ignyta’s Scientific and Clinical Presentations.