Published OnlineFirst November 24, 2009; DOI: 10.1158/1078-0432.CCR-08-2742

Molecular Pathways

Targeting the RET Pathway in Thyroid Samuel A. Wells, Jr.1 and Massimo Santoro2

Abstract The RET (rearranged during transfection) protooncogene encodes a single pass trans- membrane receptor that is expressed in cells derived from the neural crest and the uro- genital tract. As part of a cell-surface complex, RET binds glial derived neurotrophic factor (GDNF) ligands in conjunction with GDNF-family α co-receptors (GFRα). Ligand-induced activation induces dimerization and tyrosine phosphorylation of the RET receptor with downstream activation of several signal transduction pathways. Ac- tivating germline RET play a central role in the development of the multiple endocrine neoplasia (MEN) syndromes MEN2A, MEN2B, and familial medullary thyroid carcinoma (FMTC) and also in the development of the congenital abnormality Hirsch- sprung's disease. Approximately 50% of patients with sporadic MTC have somatic RET mutations, and a significant portion of papillary thyroid carcinomas result from chro- mosomal inversions or translocations, which activate RET (RET/PTC ). The RET protooncogene has a significant place in cancer prevention and treatment. Timely thyroidectomy in kindred members who have inherited a mutated RET allele, charac- teristic of MEN2A, MEN2B, or FMTC, can prevent MTC, the most common cause of death in these syndromes. Also, recently developed molecular therapeutics that target the RET pathway have shown activity in clinical trials of patients with advanced MTC, a disease for which there has been no effective therapy. (Clin Cancer Res 2009;15(23): 7119–23)

Background sine kinase, which is expressed in neuroendocrine cells (includ- Medullary thyroid carcinomas (MTC) are derived from the ing thyroid C cells and adrenal medullary cells), neural cells neural crest C cells, not from the follicular cells, as are papillary (including parasympathetic and sympathetic ganglion cells), thyroid carcinoma (PTC) and follicular thyroid carcinoma urogenital tract cells, and testis germ cells. RET is structured (FTC). The malignancy presents either sporadically (75% of with an extracellular portion (which contains four cadherin- cases) or in a hereditary pattern (25% of cases) as either multi- like repeats, a calcium , and a cysteine-rich region), ple endocrine neoplasia (MEN) type 2A, MEN2B, or familial a transmembrane portion, and an intracellular portion, which MTC (FMTC). Clinically, the hereditary forms of MTC are char- contains two subdomains (TK1 and TK2) that acterized by complete penetrance but variable expressivity, such are involved in the activation of several intracellular signal trans- that the MTC occurs in virtually all patients, however, only 50% duction pathways. Alternate splicing of RET produces three iso- of patients with MEN2A and MEN2B develop pheochromocy- forms with either 9, 43, or 51 amino acids at the C terminus, tomas, and 30% of patients with MEN2A develop parathyroid referred to as RET9, RET43, or RET51 (3). hyperplasia. Patients with FMTC only develop MTC (1). A tripartite cell-surface complex is necessary for RET signaling. The RET (rearranged during transfection) protooncogene One of four glial derived neurotrophic factor (GDNF) family li- (Fig. 1) is located in the pericentromeric region of gands (GFL), GDNF, neurturin, artemin, or persephin, binds RET 10q11.2 and spans 21 exons (2). RET encodes a receptor tyro- in conjunction with one of four glycosylphosphatidylinositol- anchored co-receptors, designated GDNF-family α receptors (GFRα): GFRα1, GFRα2, GFRα3, and GFRα4(4–8). GDNF pri- marily associates with GFRα1, whereas neurturin, artemin, and Authors' Affiliations: 1Center for Cancer Research, National Cancer persephin preferentially bind GFRα2,GFRα3, or GFRα4, respec- Institute, National Institutes of Health, Bethesda, Maryland and tively. Mice lacking GFRα4 have defects in calcitonin production, 2 Dipartimento di Biologia e Patologia, Cellulare e Molecolare, Universita' highlighting a role for the persephin receptor in regulating thyroid di Napoli “Federico II”, Naples, Italy Received 6/19/09; revised 8/27/09; accepted 8/27/09; published OnlineFirst C cell function (9). Ligand stimulation leads to activation of the 11/24/09. RET receptor with dimerization and subsequent autophosphoryla- Requests for reprints: Samuel A. Wells, Jr., Center for Cancer Research, tion of intracellular tyrosine residues, which serve as docking sites National Cancer Institute, National Institutes of Health, Building 10, Room for various adaptor (10, 11). 3-2571, 9000 Rockville Pike, Bethesda, MD 20892. Phone: 301-435-7864; Fax: 301-496-9020; E-mail: [email protected]. RET is a versatile kinase, which is capable of directly phos- F 2009 American Association for Cancer Research. phorylating multiple downstream targets (Fig. 1). Y905 is a doi:10.1158/1078-0432.CCR-08-2742 binding site for Grb7/10 adaptors, however, the function of

www.aacrjournals.org 7119Clin Cancer Res 2009 ;15(23) December 1, 2009 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2009 American Association for Cancer Research. Published OnlineFirst November 24, 2009; DOI: 10.1158/1078-0432.CCR-08-2742

Molecular Pathways

Fig. 1. The RET structure and signaling network. The structure of the RET protein and the signaling network, showing docking sites and targets. ART, artemin; NTN, neurturin; PSP, persephin; Ca++, calcium ion.

the adaptors has not been completely elucidated. The transcrip- which in turn are key regulators of receptor tyrosine kinases tion factor STAT3 is activated through phosphorylation of Y752 (15). Mice lacking RET 1015 have defects in kidney develop- and Y928. Janus kinases (JAK), c-Src, and the Ras/ERK pathway ment (16). Nonphosphotyrosine dependent mechanisms are have also been involved in STAT3 activation by different RET- involved in RET signaling as well. Phosphorylation of RET derived oncoproteins (12). Phosphorylated Y981 is the major S697 is critical for activation of the RAC1/JUN NH(2)-terminal binding site for Src, which is essential for neuronal survival. kinase (JNK) pathway and mice lacking S697 exhibit enteric Src is also necessary for RET signaling through focal adhesion nervous system defects (17). The C-tail of RET9 but not kinase (FAK), an important mediator of tumor cell migration RET51 binds the PDZ-containing scaffold protein Shank3, con- and metastases (13). RET 981 is also involved in AKT activation tributing to sustained ERK and PI3K signaling (18). (14). RET phospholipase Cγ interacts with activated RET by Finally, Y1062is a highly important multidocking binding binding Y1015, thereby activating C , site for such proteins as DOK1/4/5, Enigma, FRS2, IRS1/2,

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Targeting the RET Pathway in Thyroid Cancer

Shc, and ShcC. Phosphorylation of 1062also results in activa- of RET (39). A few patients with MEN2B have a in tion of major intracellular pathways, including RAS/ERK, PI3K/ codon 883 (exon 15; ref. 40). Single MEN2B patients with dou- AKT, nuclear factor κB (NFκB), and JNK (10, 12, 19–25). The ble RET mutations Val804Met + Ser904Cys and Val804Met + well-characterized RAS > RAF > MEK > ERK pathway plays an Tyr806Cys have been reported (41, 42). In MEN2A and FMTC important role in thyroid carcinoma as RAS mutations are the RET mutations lead to a ligand-independent homodimeri- found in FTC and in the follicular variant of PTC. BRAF muta- zation and constitutive kinase activity such that RET becomes a tions are found in PTC and anaplastic thyroid carcinoma. The dominant . In MEN2B RET mutations activate the RET role of RAS mutations in MTC is controversial (26, 27). The receptor in its monomeric state, leading to phosphorylation of PI3K > AKT pathway plays a key role in RET signaling, however, Y1062and other tyrosines, and also causing a change in sub- to date there has been little genetic analysis of this pathway strate specificity (9). in MTC. It is likely that RET does not act alone in the genesis of he- Recently, the biochemical characterization and structure of reditary MTC, and studies of MTC tissues and cell lines from the human RET tyrosine kinase domain was reported to patients with MEN2A have shown evidence of a second hit as show that both the phosphorylated and nonphosphorylated evidenced by 10 with duplication of the mutant RET forms adopt the same active kinase conformation necessary allele, loss of the wild-type RET allele, and a tandem duplica- to bind ATP and substrate and have a pre-organized activa- tion event with amplification of mutant RET (43). Almost cer- tion loop conformation that is independent of phosphoryla- tainly additional genetic defects, such as chromosomal tion status (28). deletions and amplifications will be shown in future studies. Probably, given the young age at presentation, fewer additional genetic alterations occur in MTC in patients with the germline MEN2B mutation. A recent array CGH study unveiled many Clinical-Translational Advances copy number alterations in MTC patients (44). Approxi- mately 50% of patients with sporadic MTC have somatic muta- In 1990 Grieco and associates reported that some PTCs were tions in RET codon 918 and these tumors seem to be more caused by a transforming oncogene, resulting from the rear- aggressive clinically compared with tumors lacking the somatic rangement of a heterologous amino terminal sequence to the RET mutation (45). tyrosine kinase domain of RET (29). It was subsequently shown In patients with MEN2A, MEN2B, and FMTC there is a corre- that this hybrid oncogene, termed RET/PTC, was present in ap- lation between genotype and phenotype, both in the clinical proximately 5 to 40% of PTCs and resulted from double-stranded expression of the disease spectrum and the clinical aggressive- DNA breaks with erroneous rearrangements involving the ness of MTC. Whereas, virtually all patients develop MTC, C-terminal portion of RET and the promoter and coding region pheochromocytomas develop in approximately 50% of pa- of the N terminus of a constitutively expressed unrelated gene tients with MEN2A and MEN2B. In MEN2A they occur most from chromosome 10 or a different chromosome (30). These often in patients with RET mutations in codon 634 and less fre- fusion oncogenes were found to be particularly common in quently in patients with mutations in codons 618, 620, or 791. patients previously exposed to radiation, such as the children Hyperparathyroidism occurs only in patients with MEN2A who living near the Chernobyl nuclear accident, in patients exposed have mutations in codons 618, 630, 634, or 791. Considering to external irradiation, or in victims of the atomic bomb explo- the age of onset and clinical aggressiveness of MTC, patients are sion in Japan during World War II (31–33). Spatial proximity classified as being at highest risk, higher risk, or high risk. Pa- of RET and fusion partner's loci involved in the recombination tients with MEN2B, who have mutations in codons 918 or 883 in interphase chromatin has been shown as a mechanism of represent the highest risk group, whereas patients with muta- radiation-induced recombination (34). Most PTCs, however, tions in codons 634, 630, 609, 611, 618, and 620 are in the are caused by an activating mutation in the B isoform of Raf V600E higher risk group. The high risk group includes patients with kinase, BRAF (35). PTCs caused by BRAF mutations, com- mutations in codon 768, 790, 791, 804, and 891 (46). pared with those resulting from RET/PTC translocations, are Rarely, the dermatologic disorder cutaneous lichen amyloid- larger, have a higher incidence of local tissue invasion and lymph osis and the congenital disorder Hirschsprung's disease (HSCR; node metastases, and have a poorer clinical prognosis (36). aganglionic megacolon) may occur in association with MEN2A In 1993 and 1994 it was shown that point mutations in the (46, 47). Hirschsprung's disease, the most common cause of in- RET protooncogene cause MEN2A, MEN2B, and FMTC (see testinal obstruction in the newborn, is characterized by the ab- COSMIC catalog3 and the MEN2database; 4 refs. 37, 38). sence of enteric ganglia in variable segments of intestine. A RET MEN2A is associated with mutations involving the extracellular mutation has been identified in only 50% of familial and 15 to cysteine codons 609, 611, 618, 620 (exon 10) 630, or 634 (ex- 20% of sporadic cases of HSCR (48, 49). More than 100 differ- on 11). The mutations associated with FMTC involve a broad ent RET mutations have been described, and, in contrast to mu- range of codons including some associated with MEN2A, par- tations in MEN2A, MEN2B, FMTC, and sporadic MTC, which ticularly, 609, 618, and 620, as well as others: 768, 790, and are virtually all missense mutations, they include microdele- 791 (exon 13), 804 and 844 (exon 14), or 891 (exon 15). In tions, insertions, nonsense and missense, and splicing muta- 95% of patients with MEN2B there is a point mutation in co- tions. In some cases the entire RET gene is deleted (50). The don 918 (exon 16, Met918Thr) within the intracellular domain RET mutations associated with MEN2A, MEN2B, and FMTC syndromes are generally gain-of-function mutations, whereas the RET mutations occurring in HSCR are loss-of-function mu- 3 http://www.sanger.ac.uk tations, most likely associated with a haploinsufficiency or 4 http://www.arup.utah.edu/database/MEN2/MEN2_welcome.php dominant negative effect.

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Molecular Pathways

Rarely, patients with MEN2A who have RET mutations in co- domain-containing receptor [KDR/vascular endothelial growth dons 609, 611, 618, or 620 (exon 10) develop HSCR (47). factor receptor (VEGFR2) tyrosine kinase activity (IC50 ∼ Functional studies have shown that cell surface expression of 40 nM)]. The compound also has activity against VEFGR3; these RET mutants is lower than that associated with other IC50 = 110 nM and epidermal (EGFR/ RET mutations, such as 634 (51). Thus, these four mutations HER1; IC50 = 500 nM; ref. 57). In 2002 Carlomagno and associ- lead to constitutive activation of RET and continued prolifera- ates showed that ZD6474 is a potent inhibitor (IC50 = 100 nM) tion of C cells on one hand, whereas on the other, they result in of RET oncoproteins. These investigators also found that a marked reduction of RET expression at the cell membrane, ZD6474 has a marked inhibitory effect on the growth of thy- and a resultant apoptosis of enteric neurons. roid cancer cell lines with spontaneous RET/PTC rearrange- There is no better example of the translation of genetic infor- ments and also the growth of NIH-RET/PTC xenografts (58). mation into clinical practice than that provided by detection of Phase I studies showed that ZD6474 administration is associat- RET mutations in patients with hereditary MTC. Shortly, after ed with minimal toxicity and subsequent phase II clinical trials the discovery that MEN2A, MEN2B, and FMTC were caused showed that ZD6474 has activity in patients with locally ad- by mutations in the RET protooncogene, it became clear that vanced or metastatic hereditary MTC. Approximately 20% of family members who carried a mutated RET allele could be de- patients experienced a partial remission, as shown by RECIST tected by direct DNA analysis. Knowing that the MTC was the (response evaluation criteria in solid tumors) criteria and an- most common cause of death in patients with these syndromes other 60% experienced stable disease for a disease control rate and that the thyroid gland was an expendable organ whose of 80% (59). Following treatment, there was reduction in se- function could be easily replaced by the oral administration rum levels of calcitonin and carcinoembryonic antigen, tumor of the drug thyroxin, several centers initiated screening pro- markers secreted by the MTC cells. Subsequently, it was shown grams in MEN type 2families to identify kindred members with that vandetanib induced confirmed partial remissions in 85% RET mutations. The thyroid gland can be removed safely and of children with advanced MEN2B (60). Phase II clinical trials the operation is curative if done at a young age, before the of other MTTs have also shown activity in patients with ad- MTC develops or is still confined to the thyroid gland (52, vanced MTC (61, 62). 53). Although, there is general agreement that prophylactic thy- The molecular analysis of tumor tissue in patients whose roidectomy is indicated in members of families with hereditary chronic myeloid recurred following initial treatment MTC, the timing of thyroidectomy depends on the site of the with mesylate was fundamental to the design of suc- RET codon mutation. Thyroidectomy is advised at a very early cessful rescue therapy and to the development of combinatorial age (even in the first months of life) in patients at highest risk regimens to prevent disease recurrence following primary treat- (mutations in codon 918 or 883), at 5 years of age in patients at ment (63). Unfortunately, there has been a paucity of such higher risk (mutations in codons 611, 618, 620, and 634), and studies in clinical trials of MTTs in advanced thyroid cancer, pri- between 5 and 10 years of age in patients at high risk (muta- marily because tissue acquisition has been infrequent or non- tions in codons 609, 768, 790, 791, 804, or 891; refs. 54, 55). existent. This issue must be corrected if we are to improve the The finding that the molecular targeted therapeutic (MTT) treatment of patients with this disease. STI571 (imatinib mesylate, Novartis AG) induced remissions in patients with chronic myelogenous leukemia has had a profound effect on clinical medicine and has changed the land- Disclosure of Potential Conflicts of Interest scape of cancer therapy (56). The anilinoquinazoline vandeta- S.A.Wells,Jr.,consultant,AstraZeneca.M.Santoro,commercial nib (AstraZeneca Limited) selectively inhibits the kinase insert research grant, AstraZeneca.

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www.aacrjournals.org 7123 Clin Cancer Res 2009;15(23) December 1, 2009 Downloaded from clincancerres.aacrjournals.org on September 27, 2021. © 2009 American Association for Cancer Research. Published OnlineFirst November 24, 2009; DOI: 10.1158/1078-0432.CCR-08-2742

Targeting the RET Pathway in Thyroid Cancer

Samuel A. Wells, Jr. and Massimo Santoro

Clin Cancer Res 2009;15:7119-7123. Published OnlineFirst November 24, 2009.

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