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

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

Risultato della ricerca: Article

35 Citazioni (Scopus)

Abstract

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
Volume3
Stato di pubblicazionePublished - 2014

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Molecular Chaperones
Translational Medical Research
Gene Fusion
United States Food and Drug Administration
Therapeutics
Transcriptional Activation
Lung Neoplasms
Phosphotransferases
Clinical Trials
Mutation
crizotinib
Neoplasms
isofenphos
Warfare

All Science Journal Classification (ASJC) codes

  • Oncology

Cita questo

ALK and crizotinib: After the honeymoon...what else? Resistance mechanisms and new therapies to overcome it. / Passiglia, Francesco; Castiglia, Marta; Bronte, Giuseppe; Russo, Antonio; Zwaenepoel, Karen; Gil-Bazo, Ignacio; Castiglia, Marta; Passiglia, Francesco; Pauwels, Patrick; De Wilde, Annemieke; Rolfo, Christian; Raez, Luis E.; Germonpre, Paul; Van Meerbeeck, Jan P.; Van Schil, Paul; Rolfo, Christian Diego.

In: Translational Lung Cancer Research, Vol. 3, 2014, pag. 250-261.

Risultato della ricerca: Article

Passiglia, F, Castiglia, M, Bronte, G, Russo, A, Zwaenepoel, K, Gil-Bazo, I, Castiglia, M, Passiglia, F, Pauwels, P, De Wilde, A, Rolfo, C, Raez, LE, Germonpre, P, Van Meerbeeck, JP, Van Schil, P & Rolfo, CD 2014, 'ALK and crizotinib: After the honeymoon...what else? Resistance mechanisms and new therapies to overcome it', Translational Lung Cancer Research, vol. 3, pagg. 250-261.
Passiglia, Francesco ; Castiglia, Marta ; Bronte, Giuseppe ; Russo, Antonio ; Zwaenepoel, Karen ; Gil-Bazo, Ignacio ; Castiglia, Marta ; Passiglia, Francesco ; Pauwels, Patrick ; De Wilde, Annemieke ; Rolfo, Christian ; Raez, Luis E. ; Germonpre, Paul ; Van Meerbeeck, Jan P. ; Van Schil, Paul ; Rolfo, Christian Diego. / ALK and crizotinib: After the honeymoon...what else? Resistance mechanisms and new therapies to overcome it. In: Translational Lung Cancer Research. 2014 ; Vol. 3. pagg. 250-261.
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AU - Castiglia, Marta

AU - Bronte, Giuseppe

AU - Russo, Antonio

AU - Zwaenepoel, Karen

AU - Gil-Bazo, Ignacio

AU - Castiglia, Marta

AU - Passiglia, Francesco

AU - Pauwels, Patrick

AU - De Wilde, Annemieke

AU - Rolfo, Christian

AU - Raez, Luis E.

AU - Germonpre, Paul

AU - Van Meerbeeck, Jan P.

AU - Van Schil, Paul

AU - Rolfo, Christian Diego

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N2 - 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.

AB - 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.

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