Therapeutic Targeting of Nuclear Export Inhibition in Lung Cancer

Arjun Gupta, Jessica M. Saltarski, Michael A. White, Pier P. Scaglioni, David E. Gerber

Research output: Contribution to journalArticle

6 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1446-1450
Number of pages5
JournalJournal of Thoracic Oncology
Volume12
Issue number9
DOIs
StatePublished - Sep 1 2017

Fingerprint

Cell Nucleus Active Transport
Lung Neoplasms
Tumor Suppressor Proteins
Cell Cycle
Proteinase-Activated Receptors
Topoisomerase II Inhibitors
Therapeutics
STAT3 Transcription Factor
Neoplasms
Clinical Trials, Phase I
Adenomatous Polyposis Coli
Retinoblastoma
Antineoplastic Agents
Carcinogenesis
Clinical Trials
Apoptosis
KPT-330

Keywords

  • Adenocarcinoma
  • Exportin-1
  • KRAS
  • Pathway
  • Selinexor
  • Targeted therapy
  • XPO1

ASJC Scopus subject areas

  • Oncology
  • Pulmonary and Respiratory Medicine

Cite this

Therapeutic Targeting of Nuclear Export Inhibition in Lung Cancer. / Gupta, Arjun; Saltarski, Jessica M.; White, Michael A.; Scaglioni, Pier P.; Gerber, David E.

In: Journal of Thoracic Oncology, Vol. 12, No. 9, 01.09.2017, p. 1446-1450.

Research output: Contribution to journalArticle

Gupta, Arjun ; Saltarski, Jessica M. ; White, Michael A. ; Scaglioni, Pier P. ; Gerber, David E. / Therapeutic Targeting of Nuclear Export Inhibition in Lung Cancer. In: Journal of Thoracic Oncology. 2017 ; Vol. 12, No. 9. pp. 1446-1450.
@article{4915eced800045eb94be2f71c85159da,
title = "Therapeutic Targeting of Nuclear Export Inhibition in Lung Cancer",
abstract = "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.",
keywords = "Adenocarcinoma, Exportin-1, KRAS, Pathway, Selinexor, Targeted therapy, XPO1",
author = "Arjun Gupta and Saltarski, {Jessica M.} and White, {Michael A.} and Scaglioni, {Pier P.} and Gerber, {David E.}",
year = "2017",
month = "9",
day = "1",
doi = "10.1016/j.jtho.2017.06.013",
language = "English (US)",
volume = "12",
pages = "1446--1450",
journal = "Journal of Thoracic Oncology",
issn = "1556-0864",
publisher = "International Association for the Study of Lung Cancer",
number = "9",

}

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.

PY - 2017/9/1

Y1 - 2017/9/1

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

VL - 12

SP - 1446

EP - 1450

JO - Journal of Thoracic Oncology

JF - Journal of Thoracic Oncology

SN - 1556-0864

IS - 9

ER -