Evidence map›Paper›PMID 30792533›Full record

ArticleBritish journal of cancer2019

Complementary activity of tyrosine kinase inhibitors against secondary kit mutations in imatinib-resistant gastrointestinal stromal tumours.

César Serrano, Adrián Mariño-Enríquez, Derrick L Tao, Julia Ketzer, Grant Eilers, Meijun Zhu, Channing Yu, Aristotle M Mannan, Brian P Rubin, George D Demetri and 9 more

Erratum issuedOpen access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in British journal of cancer, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 107 papers, 1 of them a synthesis that pooled it.

0numbers the graph read from it
0cells of the map it votes in
107citing papers in PubMed, 1 pooled it
14.1field-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.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

107 citing papers in PubMed, 1 synthesis or guideline pooled it, 162 citations in OpenAlex.

  1. SEOM-GEIS clinical guideline for gastrointestinal stromal tumors (2022).Clinical & translational oncology : official publication of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico · 2023
    Guideline
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  8. FDA Approval Summary: Ripretinib for Advanced Gastrointestinal Stromal Tumor.Clinical cancer research : an official journal of the American Association for Cancer Research · 2023
    Trial
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  10. Broad spectrum of regorafenib activity on mutant KIT and absence of clonal selection in gastrointestinal stromal tumor (GIST): correlative analysis from the GRID trial.Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association · 2022
    Trial
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  12. Avapritinib Versus Regorafenib in Locally Advanced Unresectable or Metastatic GI Stromal Tumor: A Randomized, Open-Label Phase III Study.Journal of clinical oncology : official journal of the American Society of Clinical Oncology · 2021
    Trial
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  15. Review
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  18. Multiomic Landscape of Gastrointestinal Stromal Tumors in a Real-World Patient Cohort of 1,427 Cases.Clinical cancer research : an official journal of the American Association for Cancer Research · 2026
    Article
  19. Article
  20. Article

47 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

19 authors at 6 institutions in 3 countries.

César SerranoDepartment of Pathology, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 528, Boston, MA, USA. cserrano@vhio.net.
Adrián Mariño-EnríquezDepartment of Pathology, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 528, Boston, MA, USA.
Derrick L TaoDepartment of Pathology, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 528, Boston, MA, USA.
Julia KetzerDepartment of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Grant EilersDepartment of Pathology, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 528, Boston, MA, USA.
Meijun ZhuDepartment of Pathology, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 528, Boston, MA, USA.
Channing YuDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Aristotle M MannanBroad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA, USA.
Brian P RubinDepartment of Molecular Genetics, Lerner Research Institute and Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH, USA.
George D DemetriDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Chandrajit P RautDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Ajia PresnellPortland VA Medical Center and OHSU Knight Cancer Institute, Portland, Oregon, USA.
Arin McKinleyPortland VA Medical Center and OHSU Knight Cancer Institute, Portland, Oregon, USA.
Michael C HeinrichPortland VA Medical Center and OHSU Knight Cancer Institute, Portland, Oregon, USA.ORCID http://orcid.org/0000-0003-3790-0478
Jeffrey T CzaplinskiDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Ewa SicinskaDepartment of Oncologic Pathology, Dana Farber Cancer Institute, Boston, MA, USA.
Sebastian BauerDepartment of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
Suzanne GeorgeDepartment of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
Jonathan A FletcherDepartment of Pathology, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 528, Boston, MA, USA. jfletcher@partners.org.
Brigham and Women's Hospital · USDana-Farber Cancer Institute · USPortland VA Medical Center · USBroad Institute · USCleveland Clinic Lerner College of Medicine · USHebron University · PS

Funding

Tissue and Pathology ResourcesP50CA127003 · NCI · DANA-FARBER CANCER INST · PI EL-BARDEESY, NABEEL, SELLERS, WILLIAM R · 2007 to 2023
$33.2M
Tissue and Pathology ResourcesU54CA168512 · NCI · SARC · PI BAKER, LAURENCE HOWARD, POLLOCK, RAPHAEL E. · 2012 to 2016
$11.0M
Regulation of oncogenic KIT by LMTK3I01BX000338 · VA · PORTLAND VA MEDICAL CENTER · PI HEINRICH, MICHAEL C · 2009 to 2019
–
BLRD VA I01 BX000338BLRD VA I01 BX005358NCI NIH HHS P50 CA127003NCI NIH HHS U54 CA168512
6 · The paper itself

Abstract

backgroundMost patients with KIT-mutant gastrointestinal stromal tumours (GISTs) benefit from imatinib, but treatment resistance results from outgrowth of heterogeneous subclones with KIT secondary mutations. Once resistance emerges, targeting KIT with tyrosine kinase inhibitors (TKIs) sunitinib and regorafenib provides clinical benefit, albeit of limited duration.

methodsWe systematically explored GIST resistance mechanisms to KIT-inhibitor TKIs that are either approved or under investigation in clinical trials: the studies draw upon GIST models and clinical trial correlative science. We subsequently modelled in vitro a rapid TKI alternation approach against subclonal heterogeneity.

resultsEach of the KIT-inhibitor TKIs targets effectively only a subset of KIT secondary mutations in GIST. Regorafenib and sunitinib have complementary activity in that regorafenib primarily inhibits imatinib-resistance mutations in the activation loop, whereas sunitinib inhibits imatinib-resistance mutations in the ATP-binding pocket. We find that rapid alternation of sunitinib and regorafenib suppresses growth of polyclonal imatinib-resistant GIST more effectively than either agent as monotherapy.

conclusionsOur data highlight that heterogeneity of KIT secondary mutations is the main mechanism of tumour progression to KIT inhibitors in imatinib-resistant GIST patients. Therapeutic combinations of TKIs with complementary activity against resistant mutations may be useful to suppress growth of polyclonal imatinib-resistance in GIST.

Indexed as

MutationAnimalsCHO CellsClinical Trials, Phase II as TopicCricetulusDrug Resistance, NeoplasmFemaleGastrointestinal NeoplasmsGastrointestinal Stromal TumorsHumansImatinib MesylateMiceMice, NudePhenylurea CompoundsProtein Kinase InhibitorsProto-Oncogene Proteins c-kitImatinib MesylateKIT protein, humanPhenylurea CompoundsProtein Kinase InhibitorsProto-Oncogene Proteins c-kitPyridinesregorafenibSunitinib

Identifiers

PMID30792533
PMCPMC6462042
OpenAlexW2916625421

What OpenQuestion holds

Textmetadata
LicenceCC BY
Read underepoch 390

Registered trials

None linked

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.