TY - JOUR
T1 - ALK fusions turn sixteen in lung cancer
T2 - a review on their biology, detection and therapy
AU - Facchinetti, Francesco
AU - Gandolfi, Laura
AU - Vasseur, Damien
AU - Melocchi, Laura
AU - Nakazawa, Seshiru
AU - Tiseo, Marcello
AU - Friboulet, Luc
AU - Rossi, Giulio
N1 - Publisher Copyright:
© AME Publishing Company.
PY - 2024/9/30
Y1 - 2024/9/30
N2 - During the last two decades, the field of targeted therapy against oncogene-driven tumors has witnessed meaningful and accelerated advancements. Ever since the discovery of ALK (anaplastic lymphoma kinase) rearrangements as driver events for non-small cell lung cancer (NSCLC) in 2007, targeting ALK has become a model of precision oncology. Especially, the recognition of crizotinib as an active and effective tyrosine kinase inhibitor (TKI) for ALK-positive NSCLC defined the proof-of-concept that ALK inhibition had important clinical value. Furthermore, a better understanding of crizotinib liabilities and resistance mechanisms prompted the development of the next generations of ALK inhibitors, leading to a shift in treatment strategy, from a sequential approach to a “new generation agents upfront” one. The continuous interrogation of resistance mechanisms to the novel inhibitors is the key feature to improving patients’ outcomes through the development of novel treatment strategies. From this perspective, the evolution of ALK inhibition in NSCLC could be defined as a cornerstone for the clinical improvements achievable in patients suffering from oncogene-driven tumors. In this review, we approach the entity of ALK fusions in lung cancer reporting the mechanisms conferring oncogenic competence, and describing the molecular diagnostic tools to detect them in the clinical practice. We then report how new generations of ALK TKIs are developed in a continuous effort to overcome the resistance to previous agents, and how these novel drugs have shaped the current therapeutic landscape for patients with ALK-positive lung cancer.
AB - During the last two decades, the field of targeted therapy against oncogene-driven tumors has witnessed meaningful and accelerated advancements. Ever since the discovery of ALK (anaplastic lymphoma kinase) rearrangements as driver events for non-small cell lung cancer (NSCLC) in 2007, targeting ALK has become a model of precision oncology. Especially, the recognition of crizotinib as an active and effective tyrosine kinase inhibitor (TKI) for ALK-positive NSCLC defined the proof-of-concept that ALK inhibition had important clinical value. Furthermore, a better understanding of crizotinib liabilities and resistance mechanisms prompted the development of the next generations of ALK inhibitors, leading to a shift in treatment strategy, from a sequential approach to a “new generation agents upfront” one. The continuous interrogation of resistance mechanisms to the novel inhibitors is the key feature to improving patients’ outcomes through the development of novel treatment strategies. From this perspective, the evolution of ALK inhibition in NSCLC could be defined as a cornerstone for the clinical improvements achievable in patients suffering from oncogene-driven tumors. In this review, we approach the entity of ALK fusions in lung cancer reporting the mechanisms conferring oncogenic competence, and describing the molecular diagnostic tools to detect them in the clinical practice. We then report how new generations of ALK TKIs are developed in a continuous effort to overcome the resistance to previous agents, and how these novel drugs have shaped the current therapeutic landscape for patients with ALK-positive lung cancer.
KW - Anaplastic lymphoma kinase (ALK)
KW - alectinib
KW - brigatinib
KW - lorlatinib
KW - tyrosine kinase inhibitors (TKIs)
UR - http://www.scopus.com/inward/record.url?scp=85199571471&partnerID=8YFLogxK
U2 - 10.21037/pcm-23-18
DO - 10.21037/pcm-23-18
M3 - Review article
AN - SCOPUS:85199571471
SN - 2617-2216
VL - 6
JO - Precision Cancer Medicine
JF - Precision Cancer Medicine
M1 - 2
ER -