65 YEARS OF THE DOUBLE HELIX: Exploiting insights on the RET receptor for personalized cancer medicine

Abstract

The focus of precision cancer medicine is the use of patient genetic signatures to predict disease occurrence and course and tailor approaches to individualized treatment to improve patient outcomes. The rearranged during transfection (RET) receptor tyrosine kinase represents a paradigm for the power of personalized cancer management to change cancer impact and improve quality of life. Oncogenic activation of RET occurs through several mechanisms including activating mutations and increased or aberrant expression. Activating RET mutations found in the inherited cancer syndrome multiple endocrine neoplasia 2 permit early diagnosis, predict disease course and guide disease management to optimize patient survival. Rearrangements of RET found in thyroid and lung tumors provide insights on potential disease aggressiveness and offer opportunities for RET-targeted therapy. Aberrant RET expression in a subset of cases is associated with tumor dissemination, resistance to therapies and/or poorer prognosis in multiple cancers. The potential of RET targeting through repurposing of small-molecule multikinase inhibitors, selective RET inhibitors or other novel approaches provides exciting opportunities to individualize therapies across multiple pathologies where RET oncogenicity contributes to cancer outcomes.

RET Gene Fusions in Malignancies of the Thyroid and Other Tissues

“…As mentioned above, the most typical oncogenic drivers of MTC, a thyroid carcinoma arising from C-cells, are RET point mutations, both in sporadic and familial cases [4][5][6][7][16][17][18]. It is worth noting that RET is normally expressed in C-cells and therefore, its oncogenic conversion does not need the acquisition of a novel transcriptional promoter caused by a gene fusion.…”

“…RET (REarranged during Transfection) was initially isolated as a rearranged oncoprotein upon the transfection of a human lymphoma DNA [1]. The RET gene maps on human chromosome 10 (at q11.21) [2] and codes for the functional tyrosine-kinase receptor (RTK) of GDNF (glial cell line-derived neurotrophic factor), Neurturin (NRT), Artemin (ART), and Persephin (PSF) growth factors [3][4][5][6][7]. These growth factors bind to auxiliary membrane-bound co-receptors, named GFRs (GDNF family receptor- [1][2][3][4]), thereby forming a bipartite complex that, in turn, mediates RET dimerization and activation [8].…”

“…Thus, tyrosines Y900, Y905, Y981, Y1015, Y1062, and Y1096 (this one is specific for RET51) have been involved in functional RET signaling. Phosphorylated tyrosine 1062 (Y1062), in particular, recruits a multitude of adaptors such as SHC1/3, FRS2, IRS1/2, and DOK1/4/5 that, in turn, mediate the activation of RAS (Rat Sarcoma)-MAPK (Mitogen-Activated Protein Kinases) and PI3K (Phosphatidylinositol-3 Kinase)-AKT (Protein Kinase B) pathways [3][4][5][6][7].…”

“…For a fully comprehensive description of the role played by RET in cancer, the reader is referred to other Reviews published on the topic (see References [4][5][6][7][16][17][18]). Moreover, comprehensive annotation of RET genetic lesions in cancer are provided by TCGA PanCancer, AACR GENIE, and MSKCC projects [19][20][21].…”

65 YEARS OF THE DOUBLE HELIX: It’s all in the DNA: understanding and managing endocrine neoplasms

“…The paradigm for endocrine neoplasia genetics begins with multiple endocrine neoplasia type 2 (MEN 2), reviewed by Lois Mulligan (Mulligan 2018), who was a co-discoverer of the first proto-oncogene cancer predisposition gene. This showed the way in molecular diagnosis, genotype-phenotype correlations and finally, medical management.…”