Therapeutic strategies in RET gene rearranged non-small cell lung cancer

Abstract

The recent approvals by the Food and Drug Administration several tumor-agnostic drugs have resulted in a paradigm shift in cancer treatment from an organ/histology-specific strategy to biomarker-guided approaches. RET gene fusions are oncogenic drivers in multiple tumor types and are known to occur in 1-2% of non-squamous NSCLC patients. RET gene fusions give rise to chimeric, cytosolic proteins with constitutively active RET kinase domain. Standard therapeutic regimens provide limited benefit for NSCLC patients with RET fusion-positive tumors, and the outcomes with immunotherapy in the these patients are generally poor. Selpercatinib (LOXO-292) and pralsetinib (BLU-667) are potent and selective inhibitors that target RET alterations, including fusions and mutations, irrespective of the tissue of origin. Recently, the results from the LIBRETTO-001 and ARROW clinical trials demonstrated significant clinical benefits with selpercatinib and pralsetinib respectively, in NSCLC patients with RET gene fusions, with tolerable toxicity profiles. These studies also demonstrated that these RET-TKIs crossed the blood brain barrier with significant activity. As has been observed with other TKIs, the emergence of acquired resistance may limit long-term efficacy of these agents. Therefore, understanding the mechanisms of resistance is necessary for the development of strategies to overcome them.

Keywords: Metastasis; Non-small cell lung cancer; RET gene fusions; Tyrosine kinase inhibitors.

Fig. 1

Mechanism of RET Gene rearrangements [12]. Models of RET rearrangements. a Schematic representation of the RET proto-oncogene (left). RET activation typically involves ligand binding, interactions with a coreceptor, and homodimerization leading to formation of a multiprotein complex (right). b Schematic representation of a KIF5B-RET fusion (left). The coiled-coil domain of KIF5B promotes ligand-independent homodimerization of RET, leading to constitutive activation of downstream growth signalling. License for reuse from John Wiley and Sons form Justin F. Gainor and Alice T. Shaw. Permission conveyed through Copyright Clearance Center, Inc. (License #: 4987820544353)