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Identification and functional characterization of STRN-ALK fusions as a therapeutic target in aggressive forms of thyroid cancer

KELLY, LINDSEY (2015) Identification and functional characterization of STRN-ALK fusions as a therapeutic target in aggressive forms of thyroid cancer. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Thyroid cancer is a common endocrine malignancy and is currently the fastest growing in incidence in the United States. Thyroid cancers encompass both well-differentiated and dedifferentiated cancer types. Dedifferentiated tumors have high mortality rates and lack effective therapies. Using paired-end whole-transcriptome RNA-sequencing of papillary thyroid cancer, we identified rearrangements involving the anaplastic lymphoma kinase (ALK) gene in thyroid cancer. We found that the most common ALK fusion in thyroid cancer is between ALK and the striatin (STRN) gene, which results from the rearrangement of chromosome 2p. STRN-ALK fusions did not overlap with other known driver mutations in these tumors, indicating that this rearrangement is a driver event. We found that the dimerization of the STRN-ALK protein by the coiled-coil domain of STRN leads to constitutive activation of ALK kinase. Our results demonstrate that STRN-ALK activation causes ALK kinase-dependent, thyroid-stimulating hormone independent proliferation of thyroid cells. We also show that STRN-ALK expression transforms cells in vitro and induces tumor formation in nude mice.
In addition to well-differentiated papillary cancer, we identified STRN-ALK with a higher frequency in poorly differentiated and anaplastic thyroid cancers. Dedifferentiation of tumors leads to loss of iodine avidity; therefore, radioiodine treatment of these tumors is no longer an option. ALK fusions are a potential molecular target for treatment of these aggressive tumors. We established that ALK inhibitors crizotinib and TAE684 block STRN-ALK kinase activity and ALK-kinase induced THS-independent thyroid cell growth in vitro. In our preclinical mouse models, growth of tumors from STRN-ALK cells is blocked by crizotinib and LDK378, FDA approved ALK inhibitors. Moreover, LDK378 halts tumor growth of crizotinib resistant STRN-ALK cells. Our data demonstrate that STRN-ALK fusions occur in a subset of patients with highly aggressive types of thyroid cancer and provide evidence that ALK represents a therapeutic target for these patients.

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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
KELLY, LINDSEYLMK66@PITT.EDULMK66
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairDeFrances, Mariedefrancesmc@upmc.eduMCD14
Committee MemberNikiforov, Yuri E.yen1@pitt.eduYEN1
Committee MemberAltschuler, Danielaltschul@pitt.eduALTSCHUL
Committee MemberZarnegar, Rezarezazar@pitt.eduREZAZAR
Committee MemberWiley, Clayton A wiley1@pitt.eduWILEY1
Committee MemberSurti, Urvashisurti@pitt.eduSURTI
Date: 6 May 2015
Date Type: Publication
Defense Date: 30 January 2015
Approval Date: 6 May 2015
Submission Date: 5 May 2015
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 108
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Cellular and Molecular Pathology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: papillary thyroid cancer, ALK gene fusions
Date Deposited: 06 May 2015 12:31
Last Modified: 19 Dec 2016 14:42
URI: http://d-scholarship.pitt.edu/id/eprint/25132

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