Targeting RET-rearranged non-small-cell lung cancer: future prospects

Giuseppe Bronte, Paola Ulivi, Alberto Verlicchi, Paola Cravero, Angelo Delmonte, Lucio Crinò Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, FC, Italy Abstract: Non-small-cell lung cancer (NSCLC) patients with mutate...

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Autores principales:	Bronte G, Ulivi P, Verlicchi A, Cravero P, Delmonte A, Crinò L
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2019
Materias:	RET non-small cell lung cancer multi-kinase inhibitors gene rearrangement Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
Acceso en línea:	https://doaj.org/article/fea97887badd4d81a5d99fd0ca558a2b
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spelling	oai:doaj.org-article:fea97887badd4d81a5d99fd0ca558a2b2021-12-02T08:37:05ZTargeting RET-rearranged non-small-cell lung cancer: future prospects1179-2728https://doaj.org/article/fea97887badd4d81a5d99fd0ca558a2b2019-03-01T00:00:00Zhttps://www.dovepress.com/targeting-ret-rearranged-non-small-cell-lung-cancer-future-prospects-peer-reviewed-article-LCTThttps://doaj.org/toc/1179-2728Giuseppe Bronte, Paola Ulivi, Alberto Verlicchi, Paola Cravero, Angelo Delmonte, Lucio Crinò Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, FC, Italy Abstract: Non-small-cell lung cancer (NSCLC) patients with mutated or rearranged oncogene drivers can be treated with upfront selective inhibitors achieving higher response rates and longer survival than chemotherapy. The RET gene can undergo chromosomal rearrangements in 1%–2% of all NSCLC patients, involving various upstream fusion partners such as KIF5B, CCDC6, NCOA4, and TRIM33. Many multikinase inhibitors are active against rearranged RET. Cabozantinib, vandetanib, sunitinib, lenvatinib, and nintedanib achieved tumor responses in about 30% of these patients in retrospective studies. Prospective phase II trials investigated the activity and toxicity of cabozantinib, vandetanib, sorafenib, and lenvatinib, and did not reach significantly higher response rates. VEGFR and EGFR inhibition represented the main ways of developing off-target toxicity. An intrinsic resistance emerged according to the type of RET fusion partners, as KIF5B-RET fusion is the most resistant. Also acquired mutations in rearranged RET oncogene developed as resistance to these multikinase inhibitors. Interestingly, RET fusions have been found as a resistance mechanism to EGFR-TKIs in EGFR-mutant NSCLC patients. The combination of EGFR and RET inhibition can overcome this resistance. The limitations in terms of activity and tolerability of the various multikinase inhibitors prompted the investigation of new highly selective RET inhibitors, such as RXDX-105, BLU-667, and LOXO-292. Some data emerged about intracranial antitumor activity of BLU-667 and LOXO-292. If these novel drugs will achieve high activity in RET rearranged NSCLC, also these oncogene-addicted tumors can undergo a significant survival improvement. Keywords: RET, non-small-cell lung cancer, multi-kinase inhibitors, gene rearrangementBronte GUlivi PVerlicchi ACravero PDelmonte ACrinò LDove Medical PressarticleRETnon-small cell lung cancermulti-kinase inhibitorsgene rearrangementNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENLung Cancer: Targets and Therapy, Vol Volume 10, Pp 27-36 (2019)
institution	DOAJ
collection	DOAJ
language	EN
topic	RET non-small cell lung cancer multi-kinase inhibitors gene rearrangement Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282
spellingShingle	RET non-small cell lung cancer multi-kinase inhibitors gene rearrangement Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Bronte G Ulivi P Verlicchi A Cravero P Delmonte A Crinò L Targeting RET-rearranged non-small-cell lung cancer: future prospects
description	Giuseppe Bronte, Paola Ulivi, Alberto Verlicchi, Paola Cravero, Angelo Delmonte, Lucio Crinò Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, FC, Italy Abstract: Non-small-cell lung cancer (NSCLC) patients with mutated or rearranged oncogene drivers can be treated with upfront selective inhibitors achieving higher response rates and longer survival than chemotherapy. The RET gene can undergo chromosomal rearrangements in 1%–2% of all NSCLC patients, involving various upstream fusion partners such as KIF5B, CCDC6, NCOA4, and TRIM33. Many multikinase inhibitors are active against rearranged RET. Cabozantinib, vandetanib, sunitinib, lenvatinib, and nintedanib achieved tumor responses in about 30% of these patients in retrospective studies. Prospective phase II trials investigated the activity and toxicity of cabozantinib, vandetanib, sorafenib, and lenvatinib, and did not reach significantly higher response rates. VEGFR and EGFR inhibition represented the main ways of developing off-target toxicity. An intrinsic resistance emerged according to the type of RET fusion partners, as KIF5B-RET fusion is the most resistant. Also acquired mutations in rearranged RET oncogene developed as resistance to these multikinase inhibitors. Interestingly, RET fusions have been found as a resistance mechanism to EGFR-TKIs in EGFR-mutant NSCLC patients. The combination of EGFR and RET inhibition can overcome this resistance. The limitations in terms of activity and tolerability of the various multikinase inhibitors prompted the investigation of new highly selective RET inhibitors, such as RXDX-105, BLU-667, and LOXO-292. Some data emerged about intracranial antitumor activity of BLU-667 and LOXO-292. If these novel drugs will achieve high activity in RET rearranged NSCLC, also these oncogene-addicted tumors can undergo a significant survival improvement. Keywords: RET, non-small-cell lung cancer, multi-kinase inhibitors, gene rearrangement
format	article
author	Bronte G Ulivi P Verlicchi A Cravero P Delmonte A Crinò L
author_facet	Bronte G Ulivi P Verlicchi A Cravero P Delmonte A Crinò L
author_sort	Bronte G
title	Targeting RET-rearranged non-small-cell lung cancer: future prospects
title_short	Targeting RET-rearranged non-small-cell lung cancer: future prospects
title_full	Targeting RET-rearranged non-small-cell lung cancer: future prospects
title_fullStr	Targeting RET-rearranged non-small-cell lung cancer: future prospects
title_full_unstemmed	Targeting RET-rearranged non-small-cell lung cancer: future prospects
title_sort	targeting ret-rearranged non-small-cell lung cancer: future prospects
publisher	Dove Medical Press
publishDate	2019
url	https://doaj.org/article/fea97887badd4d81a5d99fd0ca558a2b
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Targeting RET-rearranged non-small-cell lung cancer: future prospects

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