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Rearranged During Transfection Fusions in Non-Small Cell Lung Cancer

1
Department of Medical Oncology, Princess Alexandra Hospital, Brisbane, QLD 4102, Australia
2
Translational Research Institute, Brisbane, QLD 4102, Australia
3
Royal North Shore Hospital, Sydney, NSW 2065, Australia
*
Author to whom correspondence should be addressed.
Cancers 2019, 11(5), 620; https://doi.org/10.3390/cancers11050620
Received: 16 April 2019 / Revised: 30 April 2019 / Accepted: 30 April 2019 / Published: 3 May 2019
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Abstract

Identifying and targeting specific oncogenic drivers has become standard of care in the routine management of patients with lung cancer. Research is ongoing to expand the number of drug targets that can offer clinically meaningful outcomes. Rearranged during transfection (RET) fusions are the latest oncogenic driver alterations that show potential as a drug target. RET fusions occur in 1–2% of non-small cell lung cancer (NSCLC) cases. They are more commonly associated with younger age, female gender, non-smokers and Asian ethnicity. The RET kinase is abnormally activated through fusion with a partner protein such as KIF5B, CCDC6 or NCOA4. This leads to downstream intracellular signalling and enhancement of gene transcription and cell proliferation. The effectiveness of multi-kinase inhibitors in RET positive NSCLC has been explored in early phase and retrospective studies. From these studies, the most effective agents identified include cabozantanib and vandetanib. Overall response rates (ORR) vary from 18–47% across studies. In general, these agents have a manageable toxicity profile, although there are a number of off-target toxicities. Similar to the increased activity in ALK rearranged disease, pemetrexed has demonstrated superior response rates in this patient group and should be considered. Selective RET inhibitors, including LOXO-292 and BLU-667, are progressing in clinical trials. LOXO-292 has demonstrated an impressive ORR of 77% in RET positive solid tumours. It is anticipated this agent will be an effective targeted therapeutic option for patients with RET positive lung cancer. View Full-Text
Keywords: non-small cell lung cancer; rearranged during transfection; RET fusions non-small cell lung cancer; rearranged during transfection; RET fusions
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O’Leary, C.; Xu, W.; Pavlakis, N.; Richard, D.; O’Byrne, K. Rearranged During Transfection Fusions in Non-Small Cell Lung Cancer. Cancers 2019, 11, 620.

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