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RET Is Constitutively Activated by Novel Tandem Mutations that Alter the Active Site Resulting in Multiple Endocrine Neoplasia Type 2B

¹ Cancer Research UK Department of Oncology, Cambridge Institute for Medical Research, University of Cambridge; ² Department of Medical Genetics, Addenbrooke's Hospital, Cambridge, United Kingdom; ³ Department of Experimental Oncology, Istituto Nazionale per lo Studio e la Cura dei Tumori; ⁴ The FIRC Institute of Molecular Oncology Foundation, Milan, Italy; ⁵ Department of Chemistry and Biochemistry, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, California; ⁶ Department of Statistics and Bioinformatics Research Center, North Carolina State University, Raleigh, North Carolina; ⁷ McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland; ⁸ Division of Medical and Molecular Genetics, Guys' Tower, Guys' Hospital; and ⁹ Department of Nuclear Medicine, Guys' Hospital, London, United Kingdom

Requests for reprints: Aaron N. Cranston, Cancer Research UK Department of Oncology, Cambridge Institute for Medical Research, University of Cambridge, Hills Road, Cambridge, CB2 2XY, United Kingdom. Phone: 44-1223-336900; Fax: 44-1223-336902; E-mail: aaron.cranston{at}ntlworld.com.

Constitutive activation of the RET receptor tyrosine kinase underlies the genesis and progression of multiple endocrine neoplasia type 2 (MEN 2), a dominantly inherited cancer predisposition. Importantly, although kinase activation represents a common theme in neoplasias, not all activating mutations are functionally equivalent. Consistent with this, we ascertained a patient with classical features of MEN 2B, but lacking either of the classical mutations in RET (M918T or A883F). Instead, the patient harbors a novel pair of germ line missense mutations in cis at codons 804 and 805. We evaluated the potential physiochemical effects of these substitutions in silico, predicting both to be moderately deleterious in isolation, but severely deleterious in combination. Consistent with this postulate, we show that the identified tandem mutations (V804M/E805K) are biologically active, transforming cells in culture and that their transforming capacity in combination is distinctly synergistic. Furthermore, the V804M/E805K tandem lesion confers resistance to the small molecule receptor tyrosine kinase inhibitor, PP1, suggesting a mode of action distinct from that known for classical MEN 2B mutations. To address this question, we used homology molecular modeling in silico to model the active site of RET. We predict that RET804 constitutes a critical gatekeeper residue that, when mutated in combination with RET805, induces a conformational change in the hinge region that locks the active site in a position permissive for ATP hydrolysis. Our findings have implications both in the clinic and in the successful development of novel kinase-targeted anticancer drugs. (Cancer Res 2006; 66(20): 10179-87)

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