ALK and crizotinib: After the honeymoon...what else? Resistance mechanisms and new therapies to overcome it

Antonio Russo, Giuseppe Bronte, Francesco Passiglia, Marta Castiglia, Karen Zwaenepoel, Ignacio Gil-Bazo, Antonio Russo, Marta Castiglia, Francesco Passiglia, Patrick Pauwels, Annemieke De Wilde, Annemieke De Wilde, Christian Rolfo, Luis E. Raez, Paul Germonpre, Jan P. Van Meerbeeck, Paul Van Schil, Giuseppe Bronte, Christian Diego Rolfo

Risultato della ricerca: Articlepeer review

47 Citazioni (Scopus)


The last few decades have witnessed a silent revolution in the war against NSCLC, thanks to the discovery of "oncogenic drivers" and the subsequent development of targeted therapies. The discovery of the EML4-ALK fusion gene in a subgroup of patients with NSCLC and the subsequent clinical development of crizotinib has been an amazing success story in lung cancer translational-research, and its accelerated approval [only 4 years from the discovery of ALK rearrangement in NSCLC to the approval by the Food and Drug Administration (FDA)] marked the beginning of the new decade of targeted therapy. However, common to all targeted therapies, despite an initial benefit, patients inevitably experience tumor progression, due to the development of resistance. Several molecular mechanisms are responsible for acquired resistance, such as secondary mutations of ALK kinase domain or amplification of ALK fusion gene, or the activation of other oncogenic drivers, which may cause resistance independently of ALK genetic alterations. Pre-clinical data and early clinical trials showed the promising efficacy of a new class of ALK-inhibitors in overcoming acquired resistance. The inhibition of the molecular chaperone, HSP90, represents another promising strategy to overcome crizotinib resistance in ALK-rearranged NSCLC. Several molecules are currently under investigation in order to establish their specific role in the treatment of ALK-rearranged NSCLC.
Lingua originaleEnglish
pagine (da-a)250-261
Numero di pagine12
RivistaTranslational Lung Cancer Research
Stato di pubblicazionePublished - 2014

All Science Journal Classification (ASJC) codes

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