Evidence map›Paper›PMID 30478424›Full record

ArticleNature medicine2019

Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer.

Khyati N Shah, Roma Bhatt, Julia Rotow, Julia Rohrberg, Victor Olivas, Victoria E Wang, Golzar Hemmati, Maria M Martins, Ashley Maynard, Jonathan Kuhn and 15 more

Registry-linked trialOpen access · greenAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Nature medicine, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT04085315 (A Phase I/Ib Study of Alisertib in Combination With Osimertinib in Metastatic EGFR-mutant Lung Cancer), which is not on this map. Cited by 179 papers.

0numbers the graph read from it
0cells of the map it votes in
179citing papers in PubMed
13.6field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT04085315 phase1completednot on this map

A Phase I/Ib Study of Alisertib in Combination With Osimertinib in Metastatic EGFR-mutant Lung Cancer

TypeinterventionalSponsorCollin BlakelyRan2019 to 2025Enrolled23ConditionsLung Cancer Metastatic, EGFR Gene MutationArmsOsimertinib, Alisertib
3 · Its place in the literature

Who cites it

179 citing papers in PubMed, 281 citations in OpenAlex.

  1. Trial
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  3. Tozasertib + cisplatin inhibits proliferation, migration, and induces apoptosis in esophageal carcinoma cells.Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2026
    Article
  4. Article
  5. Article
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  7. Aurora-A drives sorafenib resistance by scaffolding stress granule assembly via phase separation.Proceedings of the National Academy of Sciences of the United States of America · 2026
    Article
  8. Article
  9. Review
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  11. Review
  12. Article
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119 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

25 authors at 2 institutions in 1 country.

Khyati N ShahDepartment of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA.ORCID http://orcid.org/0000-0002-2510-803X
Roma BhattDepartment of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA.
Julia RotowHelen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
Julia RohrbergHelen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
Victor OlivasHelen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
Victoria E WangHelen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
Golzar HemmatiHelen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
Maria M MartinsHelen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
Ashley MaynardHelen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
Jonathan KuhnDepartment of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA.
Jacqueline GaleasHelen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
Hayley J DonnellaDepartment of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA.ORCID http://orcid.org/0000-0002-9403-0192
Swati KaushikDepartment of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA.
Angel KuDepartment of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA.
Sophie DumontDepartment of Cell and Tissue Biology, University of California, San Francisco, San Francisco, CA, USA.
Gregor KringsDepartment of Pathology, University of California, San Francisco, San Francisco, CA, USA.
Henry J HaringsmaClovis Oncology, Inc., Boulder, CO, USA.
Liliane RobillardClovis Oncology, Inc., Boulder, CO, USA.
Andrew D SimmonsClovis Oncology, Inc., Boulder, CO, USA.
Thomas C HardingClovis Oncology, Inc., Boulder, CO, USA.
Frank McCormickHelen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
Andrei GogaHelen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.ORCID http://orcid.org/0000-0001-9127-0986
Collin M BlakelyHelen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.
Trever G BivonaHelen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA, USA.ORCID http://orcid.org/0000-0001-5734-4128
Sourav BandyopadhyayDepartment of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA, USA. sourav.bandyopadhyay@ucsf.edu.ORCID http://orcid.org/0000-0003-3120-923X
University of California, San Francisco · USClovis Oncology (United States) · US

Funding

UCSF Project 1U54CA224081 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Jack Roth · 2017 to 2026
$12.9M
The Cancer Target Discovery and Development Network at UCSFU01CA217882 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI BANDYOPADHYAY, SOURAV, BIVONA, TREVER G · 2017 to 2021
$5.2M
Bay Area Cancer Target Discovery and Development NetworkU01CA168370 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI MCCORMICK, FRANK PATRICK, MCMANUS, MICHAEL T · 2012 to 2016
$3.9M
Rational Combined Inhibition of NF-kB and EGFR to Optimize Lung Cancer TreatmentR01CA169338 · NCI · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI BIVONA, TREVER G · 2013 to 2023
$3.4M
Physical and Genetic Interaction Landscape of the Tyrosine KinomeR01GM107671 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI BANDYOPADHYAY, SOURAV · 2014 to 2017
$1.8M
Doris Duke Charitable Foundation 2018110NCI NIH HHS R01 CA169338NCI NIH HHS U01 CA168370NCI NIH HHS U01 CA217882NCI NIH HHS U54 CA224081NIGMS NIH HHS R01 GM107671
6 · The paper itself

Abstract

Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance.

Indexed as

Drug Resistance, NeoplasmAnimalsApoptosisAurora Kinase ACell CountCell Cycle ProteinsCell Line, TumorErbB ReceptorsHumansLung NeoplasmsMiceMicrotubule-Associated ProteinsMutationNeoplasm, ResidualNuclear ProteinsPhosphorylationAurora Kinase ACell Cycle ProteinsEGFR protein, humanErbB ReceptorsMicrotubule-Associated ProteinsNuclear ProteinsProtein Kinase InhibitorsTPX2 protein, human

Identifiers

PMID30478424
PMCPMC6324945
OpenAlexW2901591386

What OpenQuestion holds

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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.