Increased KIT Inhibition Enhances Therapeutic Efficacy in Gastrointestinal Stromal Tumor

Kim, Teresa S.; Cavnar, Michael J.; Cohen, Noah; Sorenson, Eric C.; Greer, Jonathan B.; 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; DeMatteo, Ronald P.

doi:10.1158/1078-0432.ccr-13-3033

Cited by 45 publications

(42 citation statements)

References 43 publications

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“…We tested these findings in vivo with established subcutaneous HG129 or HG209 xenografts. Imatinib only achieved stable disease in HG129 tumors as we had observed previously (28), while cabozantinib was highly effective in causing tumor regression (Fig. 5B) (mean tumor volume: vehicle 728, imatinib 313, cabozantinib 37 mm 3 , p<0.05, t -test) and decreasing KIT and Ki67 staining (Fig.…”

Section: Resultssupporting

confidence: 80%

“…Kit V558del/+ mice develop a single intestinal GIST that initially responds to imatinib therapy and then is stable in size with continued KIT activation and regrows after cessation of therapy (28). We treated Kit V558del/+ mice to ascertain if MET becomes activated in vivo after imatinib therapy.…”

Section: Resultsmentioning

confidence: 99%

“…Compensatory signaling likely explains in part why oncogene-addicted tumors such as GIST do not regress completely after pharmacologic inhibition of the driver-oncogene. Indeed, we recently reported that although the small molecule PLX3397 was a more potent KIT inhibitor than imatinib (IC 50 8 vs. 42 nM in GIST-T1 cells), it was not curative in Kit V558del/+ mice even after 19 weeks of therapy (28). It is likely that stronger KIT inhibition may induce greater systemic toxicity in patients.…”

Section: Discussionmentioning

confidence: 99%

“…GIST882, GIST-T1, and HG129 cell lines have been described (26–28). The HG209 human GIST cell line was established under an IRB-approved protocol.…”

Section: Methodsmentioning

confidence: 99%

“…Flow cytometric analysis was performed on Kit V558del/+ mouse tumors as before (28). All cells were analyzed on a FACSAria (BD Biosciences).…”

Section: Methodsmentioning

confidence: 99%

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Pharmacological Inhibition of KIT Activates MET Signaling in Gastrointestinal Stromal Tumors

et al. 2015

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Gastrointestinal stromal tumors (GIST) are the most common adult sarcomas and the oncogenic driver is usually a KIT or PDGFRA mutation. While GIST are often initially sensitive to imatinib or other tyrosine kinase inhibitors, resistance generally develops necessitating backup strategies for therapy. In this study, we determined that a subset of human GIST specimens that acquired imatinib resistance acquired expression of activated forms of the MET oncogene. MET activation also developed after imatinib therapy in a mouse model of GIST (KitV558del/+ mice), where it was associated with increased tumor hypoxia. MET activation also occurred in imatinib-sensitive human GIST cell lines after imatinib treatment in vitro. MET inhibition by crizotinib or RNA interference was cytotoxic to an imatinib-resistant human GIST cell population. Moreover, combining crizotinib and imatinib was more effective than imatinib alone in imatinib-sensitive GIST models. Lastly, cabozantinib, a dual MET and KIT small molecule inhibitor, was markedly more effective than imatinib in multiple preclinical models of imatinib-sensitive and imatinib-resistant GIST. Collectively, our findings showed that activation of compensatory MET signaling by KIT inhibition may contribute to tumor resistance. Furthermore, our work offered a preclinical proof of concept for MET inhibition by cabozantinib as an effective strategy for GIST treatment.

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Section: Resultssupporting

confidence: 80%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

“…GIST882, GIST-T1, and HG129 cell lines have been described (26–28). The HG209 human GIST cell line was established under an IRB-approved protocol.…”

Section: Methodsmentioning

confidence: 99%

“…Flow cytometric analysis was performed on Kit V558del/+ mouse tumors as before (28). All cells were analyzed on a FACSAria (BD Biosciences).…”

Section: Methodsmentioning

confidence: 99%

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Pharmacological Inhibition of KIT Activates MET Signaling in Gastrointestinal Stromal Tumors

et al. 2015

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Association of Combination of Conformation-Specific KIT Inhibitors With Clinical Benefit in Patients With Refractory Gastrointestinal Stromal Tumors

Wagner

Severson²,

Shields

et al. 2021

JAMA Oncol

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IMPORTANCEMany cancer subtypes, including KIT-mutant gastrointestinal stromal tumors (GISTs), are driven by activating mutations in tyrosine kinases and may initially respond to kinase inhibitors but frequently relapse owing to outgrowth of heterogeneous subclones with resistance mutations. KIT inhibitors commonly used to treat GIST (eg, imatinib and sunitinib) are inactive-state (type II) inhibitors.OBJECTIVE To assess whether combining a type II KIT inhibitor with a conformationcomplementary, active-state (type I) KIT inhibitor is associated with broad mutation coverage and global disease control. DESIGN, SETTING, AND PARTICIPANTSA highly selective type I inhibitor of KIT, PLX9486, was tested in a 2-part phase 1b/2a trial. Part 1 (dose escalation) evaluated PLX9486 monotherapy in patients with solid tumors. Part 2e (extension) evaluated PLX9486-sunitinib combination in patients with GIST. Patients were enrolled from March 2015 through February 2019; data analysis was performed from May 2020 through July 2020.INTERVENTIONS Participants received 250, 350, 500, and 1000 mg of PLX9486 alone (part 1) or 500 and 1000 mg of PLX9486 together with 25 or 37.5 mg of sunitinib (part 2e) continuously in 28-day dosing cycles until disease progression, treatment discontinuation, or withdrawal.MAIN OUTCOMES AND MEASURES Pharmacokinetics, safety, and tumor responses were assessed. Clinical efficacy end points (progression-free survival and clinical benefit rate) were supplemented with longitudinal monitoring of KIT mutations in circulating tumor DNA.RESULTS A total of 39 PLX9486-naive patients (median age, 57 years [range, 39-79 years]; 22 men [56.4%]; 35 [89.7%] with refractory GIST) were enrolled in the dose escalation and extension parts. The recommended phase 2 dose of PLX9486 was 1000 mg daily. At this dose, PLX9486 could be safely combined with 25 or 37.5 mg daily of sunitinib continuously. Patients with GIST who received PLX9486 at a dose of 500 mg or less, at the recommended phase 2 dose, and with sunitinib had median (95% CI) progression-free survivals of 1.74 (1.54-1.84), 5.75 (0.99-11.0), and 12.1 (1.34-NA) months and clinical benefit rates (95% CI) of 14% (0%-58%), 50% (21%-79%), and 80% (52%-96%), respectively. CONCLUSIONS AND RELEVANCEIn this phase 1b/2a nonrandomized clinical trial, type I and type II KIT inhibitors PLX9486 and sunitinib were safely coadministered at the recommended dose of both single agents in patients with refractory GIST. Results suggest that cotargeting 2 complementary conformational states of the same kinase was associated with clinical benefit with an acceptable safety profile.

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Phenotypic impacts of CSF1R deficiencies in humans and model organisms

Hume

Caruso

Ferrari-Cestari

et al. 2019

Journal of Leukocyte Biology

108

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M proliferation, differentiation, and survival are controlled by signals from the M CSF receptor (CSF1R). Mono-allelic gain-of-function mutations in CSF1R in humans are associated with an autosomal-dominant leukodystrophy and bi-allelic loss-of-function mutations with recessive skeletal dysplasia, brain disorders, and developmental anomalies. Most of the phenotypes observed in these human disease states are also observed in mice and rats with loss-of-function mutations in Csf1r or in Csf1 encoding one of its two ligands. Studies in rodent models also highlight the importance of genetic background and likely epistatic interactions between Csf1r and other loci. The impacts of Csf1r mutations on the brain are usually attributed solely to direct impacts on microglial number and function. However, analysis of hypomorphic Csf1r mutants in mice and several other lines of evidence suggest that primary hydrocephalus and loss of the physiological functions of M s in the periphery contribute to the development of brain pathology. In this review, we outline the evidence that CSF1R is expressed exclusively in mononuclear phagocytes and explore the mechanisms linking CSF1R mutations to pleiotropic impacts on postnatal growth and development.

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Increased KIT Inhibition Enhances Therapeutic Efficacy in Gastrointestinal Stromal Tumor

Cited by 45 publications

References 43 publications

Pharmacological Inhibition of KIT Activates MET Signaling in Gastrointestinal Stromal Tumors

Pharmacological Inhibition of KIT Activates MET Signaling in Gastrointestinal Stromal Tumors

Association of Combination of Conformation-Specific KIT Inhibitors With Clinical Benefit in Patients With Refractory Gastrointestinal Stromal Tumors

Phenotypic impacts of CSF1R deficiencies in humans and model organisms

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