Increased KIT inhibition enhances therapeutic efficacy in gastrointestinal stromal tumor

Teresa S. Kim, Michael J. Cavnar, Noah A. Cohen, Eric C. Sorenson, Jonathan Greer, Adrian M. Seifert, Megan H. Crawley, Benjamin L. Green, Rachel Popow, Nagavarakishore Pillarsetty, Darren R. Veach, Anson T. Ku, Ferdinand Rossi, Peter Besmer, Cristina R. Antonescu, Shan Zeng, Ronald P. De Matteo

Research output: Contribution to journalArticle

Abstract

Purpose: Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and a model of targeted molecular therapy. GIST depends on oncogenic KIT signaling and responds to the tyrosine kinase inhibitor imatinib. However, imatinib is rarely curative. We hypothesized that PLX3397, which inhibits KIT and colony-stimulating-factor-1 receptor (CSF1R), would be more efficacious than imatinib in GIST by also depleting tumor-associated macrophages, which are generally thought to support tumor growth. Experimental Design: We treated KitV558del/+ mice that develop GIST or mice with subcutaneous human GIST xenografts with imatinib or PLX3397 and analyzed tumor weight, cellular composition, histology, molecular signaling, and fibrosis. In vitro assays on human GIST cell lines were also performed. Results: PLX3397 was more effective than imatinib in reducing tumor weight and cellularity in both Kit V558del/+ murine GIST and human GIST xenografts. The superiority of PLX3397 did not depend on depletion of tumor-associated macrophages, because adding CSF1R inhibition did not improve the effects of imatinib. Instead, PLX3397 was a more potent KIT inhibitor than imatinib in vitro. PLX3397 therapy also induced substantial intratumoral fibrosis, which impaired the subsequent delivery of small molecules. Conclusions: PLX3397 therapy has greater efficacy than imatinib in preclinical GIST models and warrants study in patients with GIST. The resultant intratumoral fibrosis may represent one of the barriers to achieving complete tumor eradication.

Original languageEnglish (US)
Pages (from-to)2350-2362
Number of pages13
JournalClinical Cancer Research
Volume20
Issue number9
DOIs
StatePublished - May 1 2014
Externally publishedYes

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Gastrointestinal Stromal Tumors
Colony-Stimulating Factor Receptors
Therapeutics
Fibrosis
Macrophage Colony-Stimulating Factor
Tumor Burden
Heterografts
Neoplasms
Macrophages
Molecular Targeted Therapy
Imatinib Mesylate
Stromal Cells
5-((5-chloro-1H-pyrrolo(2,3-b)pyridin-3-yl)methyl)-N-((6-(trifluoromethyl)pyridin-3-yl)methyl)pyridin-2-amine
Tumor Cell Line
Sarcoma
Protein-Tyrosine Kinases
Histology
Research Design

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Kim, T. S., Cavnar, M. J., Cohen, N. A., Sorenson, E. C., Greer, J., Seifert, A. M., ... De Matteo, R. P. (2014). Increased KIT inhibition enhances therapeutic efficacy in gastrointestinal stromal tumor. Clinical Cancer Research, 20(9), 2350-2362. https://doi.org/10.1158/1078-0432.CCR-13-3033

Increased KIT inhibition enhances therapeutic efficacy in gastrointestinal stromal tumor. / Kim, Teresa S.; Cavnar, Michael J.; Cohen, Noah A.; Sorenson, Eric C.; Greer, Jonathan; Seifert, Adrian M.; Crawley, Megan H.; Green, Benjamin L.; Popow, Rachel; Pillarsetty, Nagavarakishore; Veach, Darren R.; Ku, Anson T.; Rossi, Ferdinand; Besmer, Peter; Antonescu, Cristina R.; Zeng, Shan; De Matteo, Ronald P.

In: Clinical Cancer Research, Vol. 20, No. 9, 01.05.2014, p. 2350-2362.

Research output: Contribution to journalArticle

Kim, TS, Cavnar, MJ, Cohen, NA, Sorenson, EC, Greer, J, Seifert, AM, Crawley, MH, Green, BL, Popow, R, Pillarsetty, N, Veach, DR, Ku, AT, Rossi, F, Besmer, P, Antonescu, CR, Zeng, S & De Matteo, RP 2014, 'Increased KIT inhibition enhances therapeutic efficacy in gastrointestinal stromal tumor', Clinical Cancer Research, vol. 20, no. 9, pp. 2350-2362. https://doi.org/10.1158/1078-0432.CCR-13-3033
Kim, Teresa S. ; Cavnar, Michael J. ; Cohen, Noah A. ; Sorenson, Eric C. ; Greer, Jonathan ; Seifert, Adrian M. ; Crawley, Megan H. ; Green, Benjamin L. ; Popow, Rachel ; Pillarsetty, Nagavarakishore ; Veach, Darren R. ; Ku, Anson T. ; Rossi, Ferdinand ; Besmer, Peter ; Antonescu, Cristina R. ; Zeng, Shan ; De Matteo, Ronald P. / Increased KIT inhibition enhances therapeutic efficacy in gastrointestinal stromal tumor. In: Clinical Cancer Research. 2014 ; Vol. 20, No. 9. pp. 2350-2362.
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T1 - Increased KIT inhibition enhances therapeutic efficacy in gastrointestinal stromal tumor

AU - Kim, Teresa S.

AU - Cavnar, Michael J.

AU - Cohen, Noah A.

AU - Sorenson, Eric C.

AU - Greer, Jonathan

AU - Seifert, Adrian M.

AU - Crawley, Megan H.

AU - Green, Benjamin L.

AU - Popow, Rachel

AU - Pillarsetty, Nagavarakishore

AU - Veach, Darren R.

AU - Ku, Anson T.

AU - Rossi, Ferdinand

AU - Besmer, Peter

AU - Antonescu, Cristina R.

AU - Zeng, Shan

AU - De Matteo, Ronald P.

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N2 - Purpose: Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and a model of targeted molecular therapy. GIST depends on oncogenic KIT signaling and responds to the tyrosine kinase inhibitor imatinib. However, imatinib is rarely curative. We hypothesized that PLX3397, which inhibits KIT and colony-stimulating-factor-1 receptor (CSF1R), would be more efficacious than imatinib in GIST by also depleting tumor-associated macrophages, which are generally thought to support tumor growth. Experimental Design: We treated KitV558del/+ mice that develop GIST or mice with subcutaneous human GIST xenografts with imatinib or PLX3397 and analyzed tumor weight, cellular composition, histology, molecular signaling, and fibrosis. In vitro assays on human GIST cell lines were also performed. Results: PLX3397 was more effective than imatinib in reducing tumor weight and cellularity in both Kit V558del/+ murine GIST and human GIST xenografts. The superiority of PLX3397 did not depend on depletion of tumor-associated macrophages, because adding CSF1R inhibition did not improve the effects of imatinib. Instead, PLX3397 was a more potent KIT inhibitor than imatinib in vitro. PLX3397 therapy also induced substantial intratumoral fibrosis, which impaired the subsequent delivery of small molecules. Conclusions: PLX3397 therapy has greater efficacy than imatinib in preclinical GIST models and warrants study in patients with GIST. The resultant intratumoral fibrosis may represent one of the barriers to achieving complete tumor eradication.

AB - Purpose: Gastrointestinal stromal tumor (GIST) is the most common human sarcoma and a model of targeted molecular therapy. GIST depends on oncogenic KIT signaling and responds to the tyrosine kinase inhibitor imatinib. However, imatinib is rarely curative. We hypothesized that PLX3397, which inhibits KIT and colony-stimulating-factor-1 receptor (CSF1R), would be more efficacious than imatinib in GIST by also depleting tumor-associated macrophages, which are generally thought to support tumor growth. Experimental Design: We treated KitV558del/+ mice that develop GIST or mice with subcutaneous human GIST xenografts with imatinib or PLX3397 and analyzed tumor weight, cellular composition, histology, molecular signaling, and fibrosis. In vitro assays on human GIST cell lines were also performed. Results: PLX3397 was more effective than imatinib in reducing tumor weight and cellularity in both Kit V558del/+ murine GIST and human GIST xenografts. The superiority of PLX3397 did not depend on depletion of tumor-associated macrophages, because adding CSF1R inhibition did not improve the effects of imatinib. Instead, PLX3397 was a more potent KIT inhibitor than imatinib in vitro. PLX3397 therapy also induced substantial intratumoral fibrosis, which impaired the subsequent delivery of small molecules. Conclusions: PLX3397 therapy has greater efficacy than imatinib in preclinical GIST models and warrants study in patients with GIST. The resultant intratumoral fibrosis may represent one of the barriers to achieving complete tumor eradication.

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