Hallmarks of RET and Co-occuring Genomic Alterations in RET-aberrant Cancers

Abstract

Activating receptor-tyrosine kinase rearranged during transfection (RET) mutations and fusions are potent drivers of oncogenesis. The recent FDA approvals of highly potent and selective RET inhibitors, selpercatinib and pralsetinib, has altered the therapeutic management of RET aberrant tumors. There is ample evidence of the role of RET signaling in certain cancers. RET aberrations as fusions or mutations occur in multiple cancers, however, there is considerable phenotypic diversity. There is emerging data on the lack of responsiveness of immunotherapy in RET-altered cancers. Herein, we review the registrational data from the selective RET-inhibitor trials, and comprehensively explore RET alterations in pan-cancer adult malignancies and their co-alterations. These co-occuring alterations may define the future of RET inhibition from specific selective targeting to customized combination therapies as data are rapidly emerging on both on-target and off-target acquired resistance mechanisms. Fascinatingly, oncogenic RET fusions have been reported to mediate resistance to EGFR inhibition and KRAS^G12C inhibition.

Figure 1.

RET gene alterations and role on other cancer-causing pathways. RET mutations are seen as germline events in hereditary MEN syndrome and somatic RET mutations are seen in sporadic MTC. RET fusions are seen in NSCLC, papillary thyroid cancer, and many other cancers.

Figure 2.

Hallmarks of RET alterations in cancer. In cell types where oncogenesis is observed there is a growing appreciation that RET's impact actually extends beyond the simple enhancing cellular proliferation, targeting additional “hallmarks” either directly or through targeting of cell-specific intracellular networks.

Figure 3.

A, Distribution of RET aberrations (excluding fusions) in AACR Genie database. Distribution of frequency of RET alterations in AACR distributed by tumor histology, correlates with Supplementary Table S2. B, Distribution of RET fusions in AACR Genie database. Distribution of frequency of RET fusions in AACR distributed by type of fusion.