Direct Targeting of RET Aberrations Moves Closer to the Clinic

William Pass, DVM
Published: Monday, Dec 10, 2018
Dr Alexander Drilon
Alexander Drilon, MD
Research on the proto-oncogene RET has accelerated exponentially since 1985, when Masahide Takahashi, MD, PhD, and colleagues first reported a fusion rearrangement in lymphoma DNA.1 Early progress was slow. Other investigators noted RET abnormalities—both fusions and mutations—in papillary thyroid cancer (PTC), in multiple endocrine neoplasia type 2 (MEN2), and after radiation exposure, but targeted interventions were still on the distant horizon.2-4

In 2005, the structure of the RET kinase domain was described, and in subsequent years, as small-molecule inhibition gained traction and RET fusions were discovered in patients with lung cancer, research on RET targeting built momentum.5 Initial multikinase inhibitor trials suggested that RET could be a viable target, but “off-target” toxicity limited effective drug design.6

In light of these findings, the focus has shifted to the development of RET-specific inhibitors. In September 2018, the leading prospect in the field, LOXO-292, was granted a breakthrough designation by the FDA for RET fusion–positive metastatic non–small cell lung cancer (NSCLC) and RET-mutant medullary thyroid cancer (MTC).7 Five weeks later, the designation was expanded to RET fusion-positive thyroid cancer.8

RET-specific inhibition appears well tolerated and effective regardless of gatekeeper mutations or RET fusion partners, and researchers are optimistic about the value of RET inhibition across tumor types. How this inhibition will be accomplished—by selective agents, custom-tailored multikinase inhibitors, or in combination with other therapies—has yet to be determined.

Pathways Involving RET

RET is a transmembrane glycoprotein receptor tyrosine kinase (RTK) encoded by RET, which is located on chromosome 10.9 During embryogenesis, RET aids in development of the enteric nervous system and kidneys; throughout life, in the homeostasis of multiple tissues.10,11

Receptor activation is achieved through indirect ligand binding; glial cell line–derived neurotrophic factor (GDNF) family ligands (GFLs) bind to GDNF family receptor-α coreceptors, resulting in a GFL–GFRα complex that homodimerizes RET.12

With homodimerization, intracellular tyrosine residues are trans-autophosphorylated, signaling adaptors are recruited, and several signaling cascades are activated. RET-associated pathways include RAS/MAPK/ERK, PI3K/AKT, JAK/STAT, and C-gamma, all of which regulate cell proliferation (Figure).13–16

RET Aberrations

With knowledge of associations between RET and downstream cell proliferation pathways, it follows logically that cancer might result from RET dysfunction. Such dysfunction can be retraced to various RET aberrations, which are divided into 2 types: chromosomal rearrangements (fusions) or mutations.1

Chromosomal rearrangements, such as the gene fusion originally described by Takahashi, most commonly lead to overexpression of RET or uncontrolled activation of the RET intracellular domain. Either mechanism can increase downstream activity, thereby contributing to malignancy via angiogenesis, cell survival, or invasion.17

Other rearrangements have also been documented, resulting in gain-of-function of RET or inhibition of tumor suppressor gene partners, but such instances are rare.18 In NSCLC, KIF5B–RET is the most common fusion, whereas CCDC6–RET and NCOA4–RET are most common in PTC.18,19 Each of these genes (KIF5B, CCDC6, NCOA4) is located on chromosome 10 with RET, and rearrangements occur via inversion.1 Rarely, interchromosomal RET rearrangements or translocations occur.17

Figure. RET Pathway Signaling Associated With Cancer13-16

Figure. RET Pathway Signaling Associated With Cancer13-16 At a population level, RET aberrations have been identified in less than 2% of diverse cancers, according to a molecular analysis of malignancies present in nearly 5000 patients. These include mutations (38.6%), fusions (30.7%), and amplifications (25%).20 RET rearrangements occur in 1% to 2% of patients with NSCLC (usually adenocarcinomas).19 These cases often share characteristics with patients who have ROS1 or ALK rearrangements; namely, that they tend to be nonsmokers less than 60 years of age.21

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