title: ALK and crizotinib: after the honeymoon…what else? Resistance mechanisms and new therapies to overcome it.
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.
authors: 1 Phase I-Early Clinical Trials Unit, Oncology Department and Multidisciplinary Oncology Center Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium ; 2 Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy ; 3 Molecular Pathology Unit, Pathology Department, Antwerp University Hospital, Edegem, Belgium ; 4 Memorial Cancer Institute, Memorial Health Care System, Florida International University, Miami, FL, USA ; 5 Thoracic Oncology Unit, Integrated Cancer Centre, AZ Maria Middelares, Gent, Belgium ; 6 Lung Cancer Unit, Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain ; 7 Thoracic Oncology, Multidisciplinary Oncology Center Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium ; 8 Thoracic Surgery Department, Antwerp University Hospital, Edegem, Belgium.
authors: Christian
authors: C
authors: Rolfo
authors: 1 Phase I-Early Clinical Trials Unit, Oncology Department and Multidisciplinary Oncology Center Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium ; 2 Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy ; 3 Molecular Pathology Unit, Pathology Department, Antwerp University Hospital, Edegem, Belgium ; 4 Memorial Cancer Institute, Memorial Health Care System, Florida International University, Miami, FL, USA ; 5 Thoracic Oncology Unit, Integrated Cancer Centre, AZ Maria Middelares, Gent, Belgium ; 6 Lung Cancer Unit, Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain ; 7 Thoracic Oncology, Multidisciplinary Oncology Center Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium ; 8 Thoracic Surgery Department, Antwerp University Hospital, Edegem, Belgium.
authors: Francesco
authors: F
authors: Passiglia
authors: 1 Phase I-Early Clinical Trials Unit, Oncology Department and Multidisciplinary Oncology Center Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium ; 2 Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy ; 3 Molecular Pathology Unit, Pathology Department, Antwerp University Hospital, Edegem, Belgium ; 4 Memorial Cancer Institute, Memorial Health Care System, Florida International University, Miami, FL, USA ; 5 Thoracic Oncology Unit, Integrated Cancer Centre, AZ Maria Middelares, Gent, Belgium ; 6 Lung Cancer Unit, Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain ; 7 Thoracic Oncology, Multidisciplinary Oncology Center Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium ; 8 Thoracic Surgery Department, Antwerp University Hospital, Edegem, Belgium.
authors: Marta
authors: M
authors: Castiglia
authors: 1 Phase I-Early Clinical Trials Unit, Oncology Department and Multidisciplinary Oncology Center Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium ; 2 Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy ; 3 Molecular Pathology Unit, Pathology Department, Antwerp University Hospital, Edegem, Belgium ; 4 Memorial Cancer Institute, Memorial Health Care System, Florida International University, Miami, FL, USA ; 5 Thoracic Oncology Unit, Integrated Cancer Centre, AZ Maria Middelares, Gent, Belgium ; 6 Lung Cancer Unit, Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain ; 7 Thoracic Oncology, Multidisciplinary Oncology Center Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium ; 8 Thoracic Surgery Department, Antwerp University Hospital, Edegem, Belgium.
authors: Luis E
authors: LE
authors: Raez
authors: 1 Phase I-Early Clinical Trials Unit, Oncology Department and Multidisciplinary Oncology Center Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium ; 2 Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy ; 3 Molecular Pathology Unit, Pathology Department, Antwerp University Hospital, Edegem, Belgium ; 4 Memorial Cancer Institute, Memorial Health Care System, Florida International University, Miami, FL, USA ; 5 Thoracic Oncology Unit, Integrated Cancer Centre, AZ Maria Middelares, Gent, Belgium ; 6 Lung Cancer Unit, Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain ; 7 Thoracic Oncology, Multidisciplinary Oncology Center Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium ; 8 Thoracic Surgery Department, Antwerp University Hospital, Edegem, Belgium.
authors: Paul
authors: P
authors: Germonpre
authors: 1 Phase I-Early Clinical Trials Unit, Oncology Department and Multidisciplinary Oncology Center Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium ; 2 Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy ; 3 Molecular Pathology Unit, Pathology Department, Antwerp University Hospital, Edegem, Belgium ; 4 Memorial Cancer Institute, Memorial Health Care System, Florida International University, Miami, FL, USA ; 5 Thoracic Oncology Unit, Integrated Cancer Centre, AZ Maria Middelares, Gent, Belgium ; 6 Lung Cancer Unit, Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain ; 7 Thoracic Oncology, Multidisciplinary Oncology Center Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium ; 8 Thoracic Surgery Department, Antwerp University Hospital, Edegem, Belgium.
authors: Ignacio
authors: I
authors: Gil-Bazo
authors: 1 Phase I-Early Clinical Trials Unit, Oncology Department and Multidisciplinary Oncology Center Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium ; 2 Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy ; 3 Molecular Pathology Unit, Pathology Department, Antwerp University Hospital, Edegem, Belgium ; 4 Memorial Cancer Institute, Memorial Health Care System, Florida International University, Miami, FL, USA ; 5 Thoracic Oncology Unit, Integrated Cancer Centre, AZ Maria Middelares, Gent, Belgium ; 6 Lung Cancer Unit, Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain ; 7 Thoracic Oncology, Multidisciplinary Oncology Center Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium ; 8 Thoracic Surgery Department, Antwerp University Hospital, Edegem, Belgium.
authors: Karen
authors: K
authors: Zwaenepoel
authors: 1 Phase I-Early Clinical Trials Unit, Oncology Department and Multidisciplinary Oncology Center Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium ; 2 Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy ; 3 Molecular Pathology Unit, Pathology Department, Antwerp University Hospital, Edegem, Belgium ; 4 Memorial Cancer Institute, Memorial Health Care System, Florida International University, Miami, FL, USA ; 5 Thoracic Oncology Unit, Integrated Cancer Centre, AZ Maria Middelares, Gent, Belgium ; 6 Lung Cancer Unit, Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain ; 7 Thoracic Oncology, Multidisciplinary Oncology Center Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium ; 8 Thoracic Surgery Department, Antwerp University Hospital, Edegem, Belgium.
authors: Annemieke
authors: A
authors: De Wilde
authors: 1 Phase I-Early Clinical Trials Unit, Oncology Department and Multidisciplinary Oncology Center Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium ; 2 Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy ; 3 Molecular Pathology Unit, Pathology Department, Antwerp University Hospital, Edegem, Belgium ; 4 Memorial Cancer Institute, Memorial Health Care System, Florida International University, Miami, FL, USA ; 5 Thoracic Oncology Unit, Integrated Cancer Centre, AZ Maria Middelares, Gent, Belgium ; 6 Lung Cancer Unit, Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain ; 7 Thoracic Oncology, Multidisciplinary Oncology Center Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium ; 8 Thoracic Surgery Department, Antwerp University Hospital, Edegem, Belgium.
authors: Giuseppe
authors: G
authors: Bronte
authors: 1 Phase I-Early Clinical Trials Unit, Oncology Department and Multidisciplinary Oncology Center Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium ; 2 Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy ; 3 Molecular Pathology Unit, Pathology Department, Antwerp University Hospital, Edegem, Belgium ; 4 Memorial Cancer Institute, Memorial Health Care System, Florida International University, Miami, FL, USA ; 5 Thoracic Oncology Unit, Integrated Cancer Centre, AZ Maria Middelares, Gent, Belgium ; 6 Lung Cancer Unit, Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain ; 7 Thoracic Oncology, Multidisciplinary Oncology Center Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium ; 8 Thoracic Surgery Department, Antwerp University Hospital, Edegem, Belgium.
authors: Antonio
authors: A
authors: Russo
authors: 1 Phase I-Early Clinical Trials Unit, Oncology Department and Multidisciplinary Oncology Center Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium ; 2 Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy ; 3 Molecular Pathology Unit, Pathology Department, Antwerp University Hospital, Edegem, Belgium ; 4 Memorial Cancer Institute, Memorial Health Care System, Florida International University, Miami, FL, USA ; 5 Thoracic Oncology Unit, Integrated Cancer Centre, AZ Maria Middelares, Gent, Belgium ; 6 Lung Cancer Unit, Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain ; 7 Thoracic Oncology, Multidisciplinary Oncology Center Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium ; 8 Thoracic Surgery Department, Antwerp University Hospital, Edegem, Belgium.
authors: Jan P
authors: JP
authors: Van Meerbeeck
authors: 1 Phase I-Early Clinical Trials Unit, Oncology Department and Multidisciplinary Oncology Center Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium ; 2 Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy ; 3 Molecular Pathology Unit, Pathology Department, Antwerp University Hospital, Edegem, Belgium ; 4 Memorial Cancer Institute, Memorial Health Care System, Florida International University, Miami, FL, USA ; 5 Thoracic Oncology Unit, Integrated Cancer Centre, AZ Maria Middelares, Gent, Belgium ; 6 Lung Cancer Unit, Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain ; 7 Thoracic Oncology, Multidisciplinary Oncology Center Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium ; 8 Thoracic Surgery Department, Antwerp University Hospital, Edegem, Belgium.
authors: Paul
authors: P
authors: Van Schil
authors: 1 Phase I-Early Clinical Trials Unit, Oncology Department and Multidisciplinary Oncology Center Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium ; 2 Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy ; 3 Molecular Pathology Unit, Pathology Department, Antwerp University Hospital, Edegem, Belgium ; 4 Memorial Cancer Institute, Memorial Health Care System, Florida International University, Miami, FL, USA ; 5 Thoracic Oncology Unit, Integrated Cancer Centre, AZ Maria Middelares, Gent, Belgium ; 6 Lung Cancer Unit, Department of Oncology, Clinica Universidad de Navarra, Pamplona, Spain ; 7 Thoracic Oncology, Multidisciplinary Oncology Center Antwerp (MOCA), Antwerp University Hospital, Edegem, Belgium ; 8 Thoracic Surgery Department, Antwerp University Hospital, Edegem, Belgium.
authors: Patrick
authors: P
authors: Pauwels
keywords: ALK inhibitors; ALK rearrangements; NSCLC; resistance