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- Title
RET Inhibitors in Non-Small-Cell Lung Cancer.
- Authors
Cascetta, Priscilla; Sforza, Vincenzo; Manzo, Anna; Carillio, Guido; Palumbo, Giuliano; Esposito, Giovanna; Montanino, Agnese; Costanzo, Raffaele; Sandomenico, Claudia; De Cecio, Rossella; Piccirillo, Maria Carmela; La Manna, Carmine; Totaro, Giuseppe; Muto, Paolo; Picone, Carmine; Bianco, Roberto; Normanno, Nicola; Morabito, Alessandro
- Abstract
Simple Summary: Non-small cell lung cancer (NSCLC) remains a significant cause of death worldwide, despite the significant progresses to date. Multiple molecular alterations have been identified in NSCLC, leading to the development of target-based agents that have shown significant clinical benefits. Rearranged during Transfection (RET) fusions have recently emerged as a new potential target and a number of non-selective and selective RET inhibitors have been tested in RET positive NSCLC. In this review we analyse and summarise the characteristics of RET functions and its alterations in NSCLC. We then present the state of the art RET inhibitors in the treatment of NSCLC, discussing the ongoing trials and the future perspectives for RET positive (RET+) NSCLC patients. RET rearrangements are observed in 1–2% of non-small-cell lung cancer (NSCLC) patients and result in the constitutive activation of downstream pathways normally implied in cell proliferation, growth, differentiation and survival. In NSCLC patients, RET rearrangements have been associated with a history of non-smoking, a higher rate of brain metastasis at initial diagnosis and a low immune infiltrate. Traditionally, RET fusions are considered mutually exclusive with other oncogenic drivers, even though a co-occurrence with EGFR mutations and MET amplifications has been observed. Cabozantinib, vandetanib and lenvatinib are the first multi-kinase inhibitors tested in RET-rearranged NSCLC patients with contrasting results. More recently, two selective RET inhibitors, selpercatinib and pralsetinib, demonstrated higher efficacy rates and good tolerability and they were approved for the treatment of patients with metastatic RET fusion-positive NSCLC on the bases of the results of phase II studies. Two ongoing phase III clinical trials are currently comparing selpercatinib or pralsetinib to standard first line treatments and will definitively establish their efficacy in RET-positive NSCLC patients.
- Subjects
BRAIN tumor risk factors; LUNG cancer; CELL differentiation; GENETIC mutation; DRUG tolerance; PROTEIN kinase inhibitors; ONCOGENES; CELL physiology; TREATMENT effectiveness; CELL survival; CELLULAR signal transduction; CELL proliferation; NUCLEIC acid amplification techniques
- Publication
Cancers, 2021, Vol 13, Issue 17, p4415
- ISSN
2072-6694
- Publication type
Article
- DOI
10.3390/cancers13174415