Inhibition of FGF receptor blocks adaptive resistance to RET inhibition in CCDC6-RET–rearranged thyroid cancer

Abstract

Genetic alterations in RET lead to activation of ERK and AKT signaling and are associated with hereditary and sporadic thyroid cancer and lung cancer. Highly selective RET inhibitors have recently entered clinical use after demonstrating efficacy in treating patients with diverse tumor types harboring RET gene rearrangements or activating mutations. In order to understand resistance mechanisms arising after treatment with RET inhibitors, we performed a comprehensive molecular and genomic analysis of a patient with RET-rearranged thyroid cancer. Using a combination of drug screening and proteomic and biochemical profiling, we identified an adaptive resistance to RET inhibitors that reactivates ERK signaling within hours of drug exposure. We found that activation of FGFR signaling is a mechanism of adaptive resistance to RET inhibitors that activates ERK signaling. Combined inhibition of FGFR and RET prevented the development of adaptive resistance to RET inhibitors, reduced cell viability, and decreased tumor growth in cellular and animal models of CCDC6-RET–rearranged thyroid cancer.

Selpercatinib combination with the mitochondria-targeted antioxidant MitoQ effectively suppresses RET–mutant thyroid cancer

“…1a ). Western blot analysis of these cells revealed that selpercatinib substantially decreased RET phosphorylation at Tyr905, an activating autophosphorylation 16 , 41 , 42 , and phosphorylation of ERK1/2 and AKT, the key downstream effectors of RET 16 , while increasing expression of the cyclin-dependent kinase inhibitor p27 KIP1 but decreasing p21 CIP1 expression (Supplementary Fig. 1b, c ).…”

“…Somatic and germline RET mutations leading to constitutive RET activation are also found in cancers, including multiple endocrine neoplasia type 2 A and 2B (MEN2A and MEN2B) syndromes and familial medullary thyroid carcinoma (MTC) 14 , 15 . Upon activation, RET promotes various cellular processes, including cell growth, proliferation, and survival, mainly through the mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK), the phosphatidylinositol-3 kinase/protein kinase B (AKT) 16 , and the Janus kinase/signal transducer and activator of transcription pathways 2 .…”

Targeted therapy of RET fusion-positive non-small cell lung cancer

“…Cabozantinib combined with everolimus improves the therapeutic effect of advanced renal cell carcinoma ( 111 , 112 ), which may be a revelation of treatment for patients with RET fusion-positive NSCLC. An important research ( 113 ) result in thyroid cancer, inhibition of FGF receptor blocks adaptive resistance to RET inhibition in CCDC6-RET-rearranged thyroid cancer. This may also be replicated in RET fusion-positive NSCLC.…”