TY - JOUR
T1 - Therapeutic Targeting of Nuclear Export Inhibition in Lung Cancer
AU - Gupta, Arjun
AU - Saltarski, Jessica M.
AU - White, Michael A.
AU - Scaglioni, Pier P.
AU - Gerber, David E.
N1 - Funding Information:
This study was Funded in part by a National Cancer Institute Midcareer Investigator Award in Patient-Oriented Research (K24CA201543-01 to Dr. Gerber).
Publisher Copyright:
© 2017 International Association for the Study of Lung Cancer
PY - 2017/9
Y1 - 2017/9
N2 - Intracellular compartmentalization and trafficking of molecules plays a critical role in complex and essential cellular processes. In lung cancer and other malignancies, aberrant nucleocytoplasmic transport of tumor suppressor proteins and cell cycle regulators results in tumorigenesis and inactivation of apoptosis. Pharmacologic agents targeting this process, termed selective inhibitors of nuclear export (SINE), have demonstrated antitumor efficacy in preclinical models and human clinical trials. Exportin-1 (XPO1), which serves as the sole exporter of several tumor suppressor proteins and cell cycle regulators, including retinoblastoma, adenomatous polyposis coli, p53, p73, p21, p27, forkhead box O, signal transducer and activator of transcription 3, inhibitor of κB, topoisomerase II, and protease activated receptor 4—is the principal focus of development of SINE. The most extensively studied of the SINE to date, the exportin-1 inhibitor selinexor (KPT-330 [Karyopharm Therapeutics, Inc., Newton Centre, MA]), has demonstrated single-agent anticancer activity and synergistic effects in combination regimens against multiple cancer types, with principal toxicities of low-grade cytopenias and gastrointestinal effects. SINE may have particular relevance in KRAS-driven tumors, for which this treatment strategy demonstrates significant synthetic lethality. A multicenter phase 1/2 clinical trial of selinexor in previously treated advanced KRAS-mutant NSCLC is under way.
AB - Intracellular compartmentalization and trafficking of molecules plays a critical role in complex and essential cellular processes. In lung cancer and other malignancies, aberrant nucleocytoplasmic transport of tumor suppressor proteins and cell cycle regulators results in tumorigenesis and inactivation of apoptosis. Pharmacologic agents targeting this process, termed selective inhibitors of nuclear export (SINE), have demonstrated antitumor efficacy in preclinical models and human clinical trials. Exportin-1 (XPO1), which serves as the sole exporter of several tumor suppressor proteins and cell cycle regulators, including retinoblastoma, adenomatous polyposis coli, p53, p73, p21, p27, forkhead box O, signal transducer and activator of transcription 3, inhibitor of κB, topoisomerase II, and protease activated receptor 4—is the principal focus of development of SINE. The most extensively studied of the SINE to date, the exportin-1 inhibitor selinexor (KPT-330 [Karyopharm Therapeutics, Inc., Newton Centre, MA]), has demonstrated single-agent anticancer activity and synergistic effects in combination regimens against multiple cancer types, with principal toxicities of low-grade cytopenias and gastrointestinal effects. SINE may have particular relevance in KRAS-driven tumors, for which this treatment strategy demonstrates significant synthetic lethality. A multicenter phase 1/2 clinical trial of selinexor in previously treated advanced KRAS-mutant NSCLC is under way.
KW - Adenocarcinoma
KW - Exportin-1
KW - KRAS
KW - Pathway
KW - Selinexor
KW - Targeted therapy
KW - XPO1
UR - http://www.scopus.com/inward/record.url?scp=85025434328&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85025434328&partnerID=8YFLogxK
U2 - 10.1016/j.jtho.2017.06.013
DO - 10.1016/j.jtho.2017.06.013
M3 - Article
C2 - 28647672
AN - SCOPUS:85025434328
SN - 1556-0864
VL - 12
SP - 1446
EP - 1450
JO - Journal of Thoracic Oncology
JF - Journal of Thoracic Oncology
IS - 9
ER -