Rearrangements of RET are drivers of oncogenesis, traceable in different cancer types as papillary thyroid carcinoma (PTC), non-small cell lung cancer, colorectal or breast cancer.
After determining the MTD and RP2D, an expansion in non-small-cell lung cancer (NSCLC) consisting of 3 molecularly defined cohorts (EGFR mutation; KRAS mutation; ALK, RET, or ROS1 fusion) was initiated.
Cabozantinib, an orally bioavailable tyrosine kinase inhibitor with activity against MET, vascular endothelial growth factor receptor 2, AXL, ROS1, and RET was assessed in patients with non-small-cell lung carcinoma (NSCLC) as part of a phase II randomized discontinuation trial with cohorts from 9 tumor types.
The impressive clinical activity of small-molecule receptor tyrosine kinase inhibitors for oncogene-addicted subgroups of non-small-cell lung cancer (for example, those driven by activating mutations in the gene encoding epidermal growth factor receptor (EGFR) or rearrangements in the genes encoding the receptor tyrosine kinases anaplastic lymphoma kinase (ALK), ROS proto-oncogene 1 (ROS1) and rearranged during transfection (RET)) has established an oncogene-centric molecular classification paradigm in this disease.
RET-positive expression is a relatively independent factor in NSCLC patients, which indicates that the RET gene may be a novel target site for personalized treatment of NSCLC.
CONCLUSIONS The results of this research indicate that the metastases of non-small cell lung cancer can predict RET rearrangement of the primary tumor tissue in the majority of cases.
In tumor cell lines displaying molecular alterations in potential nintedanib targets, the inhibitor demonstrates direct antiproliferative effects: in the NSCLC cell line NCI-H1703 carrying a PDGFR<i>α</i> amplification (ampl.); the gastric cancer cell line KatoIII and the breast cancer cell line MFM223, both driven by a FGFR2 amplification; AN3CA (endometrial carcinoma) bearing a mutated FGFR2; the acute myeloid leukemia cell lines MOLM-13 and MV-4-11-B with FLT3 mutations; and the NSCLC adenocarcinoma LC-2/ad harboring a CCDC6-RET fusion.
While RET TK inhibitors (TKIs) are used to treat thyroid cancer and are in clinical trials for RET fusion-positive non-small cell lung cancer, the impact of mutations in the RET kinase domain on drug sensitivity is largely uncharacterized.
Our case expands the spectrum of RET fusion partners and supports broad molecular profiling in non-small cell lung cancer optimizing patient therapeutic options.
In first-in-human testing, BLU-667 significantly inhibited RET signaling and induced durable clinical responses in patients with <i>RET</i>-altered NSCLC and MTC without notable off-target toxicity, providing clinical validation for selective RET targeting.<b>Significance:</b> Patients with <i>RET</i>-driven cancers derive limited benefit from available MKIs.
Advanced RET-rearranged NSCLC manifested as a relatively small and peripherally located solid primary lesion with or without small solitary lymphadenopathy.
Since the discovery in 2012 of rearranged during transfection proto-oncogene gene (RET) rearrangements in NSCLC, at least 12 different fusion variants have been identified, with kinesin family member 5B gene (KIF5B)-RET being the most frequent and the best characterized.
In this open-label, multicentre, phase 2 trial (LURET), patients with advanced RET-rearranged NSCLC continuously received 300 mg of oral vandetanib daily.
Anaplastic lymphoma receptor tyrosine kinase (<i>ALK</i>), ROS proto-oncogene 1, receptor tyrosine kinase (<i>ROS1</i>), and ret proto-oncogene (<i>RET</i>) fusions are present in 5%-7% of patients with advanced non-small-cell lung cancer (NSCLC); their accurate identification is critical to guide targeted therapies.
ALK, ROS1 and RET rearrangements were screened by reverse transcriptase polymerase chain reaction (RT-PCR) in patients with completely resected non-adenocarcinoma NSCLC.