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Br J Cancer. 2019 Mar;120(6):612-620. doi: 10.1038/s41416-019-0389-6. Epub 2019 Feb 22.

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

Author information

1
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 528, Boston, MA, USA. cserrano@vhio.net.
2
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. cserrano@vhio.net.
3
Sarcoma Translational Research Laboratory, Vall d'Hebron Institute of Oncology; Department of Oncology, Vall d'Hebron University Hospital, Barcelona, Spain. cserrano@vhio.net.
4
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 528, Boston, MA, USA.
5
Department of Medical Oncology, West German Cancer Center, University Hospital Essen, University Duisburg-Essen, Essen, Germany.
6
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
7
Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, MA, USA.
8
Daiichi Sankyo Inc., Basking Ridge, NJ, USA.
9
Department of Molecular Genetics, Lerner Research Institute and Cleveland Clinic, 9500 Euclid Ave, Cleveland, OH, USA.
10
Ludwig Center for Cancer Research at Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
11
Division of Surgical Oncology, Brigham and Women's Hospital, Harvard Medical School, Boston, 75 Francis Street, Boston, MA, USA.
12
Portland VA Medical Center and OHSU Knight Cancer Institute, Portland, Oregon, USA.
13
Department of Oncologic Pathology, Dana Farber Cancer Institute, Boston, MA, USA.
14
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 20 Shattuck Street, Thorn 528, Boston, MA, USA. jfletcher@partners.org.
15
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. jfletcher@partners.org.

Abstract

BACKGROUND:

Most 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.

METHODS:

We 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.

RESULTS:

Each 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.

CONCLUSIONS:

Our 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.

PMID:
30792533
DOI:
10.1038/s41416-019-0389-6

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