Dataset Information

Identification of Wee1 as a target in combination with avapritinib for gastrointestinal stromal tumor treatment.

ABSTRACT: Management of gastrointestinal stromal tumors (GISTs) has been revolutionized by the identification of activating mutations in KIT and PDGFRA and clinical application of RTK inhibitors in advanced disease. Stratification of GISTs into molecularly defined subsets provides insight into clinical behavior and response to approved targeted therapies. Although these RTK inhibitors are effective in most GISTs, resistance remains a significant clinical problem. Development of effective treatment strategies for refractory GISTs requires identification of novel targets to provide additional therapeutic options. Global kinome profiling has the potential to identify critical signaling networks and reveal protein kinases essential in GISTs. Using multiplexed inhibitor beads and mass spectrometry, we explored the majority of the kinome in GIST specimens from the 3 most common molecular subtypes (KIT mutant, PDGFRA mutant, and succinate dehydrogenase deficient) to identify kinase targets. Kinome profiling with loss-of-function assays identified an important role for G2/M tyrosine kinase, Wee1, in GIST cell survival. In vitro and in vivo studies revealed significant efficacy of MK-1775 (Wee1 inhibitor) in combination with avapritinib in KIT mutant and PDGFRA mutant GIST cell lines as well as notable efficacy of MK-1775 as a monotherapy in the engineered PDGFRA mutant line. These studies provide strong preclinical justification for the use of MK-1775 in GIST.

SUBMITTER: Ye S

PROVIDER: S-EPMC7934848 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Identification of Wee1 as a target in combination with avapritinib for gastrointestinal stromal tumor treatment.

Ye Shuai S Sharipova Dinara D Kozinova Marya M Klug Lilli L D'Souza Jimson J Belinsky Martin G MG Johnson Katherine J KJ Einarson Margret B MB Devarajan Karthik K Zhou Yan Y Litwin Samuel S Heinrich Michael C MC DeMatteo Ronald R von Mehren Margaret M Duncan James S JS Rink Lori L

JCI insight 20210125 2

Management of gastrointestinal stromal tumors (GISTs) has been revolutionized by the identification of activating mutations in KIT and PDGFRA and clinical application of RTK inhibitors in advanced disease. Stratification of GISTs into molecularly defined subsets provides insight into clinical behavior and response to approved targeted therapies. Although these RTK inhibitors are effective in most GISTs, resistance remains a significant clinical problem. Development of effective treatment strateg ...[more]

PMID: 33320833

Similar Datasets

Project description:BackgroundAvapritinib, a novel inhibitor of KIT/PDGFRA, is approved in the U.S. for the treatment of adults with PDGFRA exon 18-mutant unresectable or metastatic gastrointestinal stromal tumors (U/M GISTs). We assessed the safety of avapritinib and provide evidence-based guidance on management of avapritinib-associated adverse events (AEs), including cognitive effects and intracranial bleeding.Materials and methodsWe performed a post hoc analysis of data from a two-part, single-arm dose escalation/expansion phase I study (NAVIGATOR; NCT02508532) in patients with U/M GISTs treated with oral avapritinib 30-600 mg once daily. The primary endpoints were safety and tolerability; the impact of dose modification (interruption and/or reduction) on progression-free survival (PFS) was a secondary endpoint. Efficacy analyses were limited to patients who started avapritinib at 300 mg (approved dose).ResultsOf 250 patients enrolled in the study, 74.0% presented with KIT mutation and 24.8% presented with PDGFRA exon 18-mutation; 66.8% started avapritinib at 300 mg. The most common treatment-related AEs (any grade) were nausea (59.2%), fatigue (50.0%), periorbital edema (42.0%), anemia (39.2%), diarrhea (36.0%), vomiting (36.0%), and increased lacrimation (30.8%). No treatment-related deaths occurred. Among 167 patients starting on 300 mg avapritinib, all-cause cognitive effects rate (grade 1-2) was 37.0% in all patients and 52.0% in patients ≥65 years. Cognitive effects improved to a lower grade more quickly with dose modification (1.3-3.1 weeks) than without (4.9-7.6 weeks). Median PFS was 11.4 months with dose modification and 7.2 months without.ConclusionTolerability-guided dose modification of avapritinib is an effective strategy for managing AEs in patients with GISTs.Implications for practiceEarly recognition of adverse events and tailored dose modification appear to be effective approaches for managing treatment-related adverse events and maintaining patients on avapritinib. Dose reduction does not appear to result in reduced efficacy. Patients' cognitive function should be assessed at baseline and monitored carefully throughout treatment with avapritinib for the onset of cognitive adverse events. Dose interruption is recommended at the first sign of any cognitive effect, including grade 1 events.

Project description:Background Tyrosine kinase inhibitors (TKIs) are currently the main treatment choice for gastrointestinal stromal tumors (GISTs). However, the long-term use of TKIs can lead to drug resistance. There is no study or clinical report of combination therapies of TKIs that have been approved for marketing. Combination pharmacotherapy is a new approach for patients who do not respond to monotherapy. This case provides a reference value for selective combination of TKIs in treating advanced GIST. Case Description In this article, we report the case of a 55-year-old female who was diagnosed with duodenal GIST in April 2018 and underwent R0 resection. KIT exon 9 mutation was detected. The patient had disease recurrence with multiple abdominal metastases during imatinib adjuvant therapy after 27 months, and failure to 2nd-line sunitinib treatment after 6 months. She underwent a cytoreductive surgery (R1), and the postoperative mutation analysis suggested KIT exon 9 mutation, with newly found secondary KIT_exon16_p. L783V mutation and other mutations on TP53, POT1, and SETD2, etc. The patient experienced short-term tumor control of standard 3rd-line therapy of regorafenib and the rapid progression of the 4th-line of ripretinib afterwards. Different TKI combination therapies (i.e., ripretinib plus sunitinib, ripretinib plus avapritinib and avapritinib plus sunitinib) were administered to the patient sequentially. Ripretinib plus sunitinib led to stable disease but was discontinued due to intolerable adverse effects. Finally, the patient received a combination regimen of avapritinib plus sunitinib. The patient’s tumor showed continuous shrinking in 2 consecutive computed tomography scan evaluations within 4 months with acceptable side effects. Conclusions Combined type I and type II TKIs of avapritinib combined with sunitinib therapy achieved tumor regression for a heavily multi-line treated patient. Our case provides a reference for a savage treatment choice in refractory GISTs after failure to all standard treatment.

Project description:BackgroundMost gastrointestinal stromal tumors (GIST) driven by KIT or platelet-derived growth factor receptor A (PDGFRA) mutations develop resistance to available tyrosine kinase inhibitor (TKI) treatments. NAVIGATOR is a two-part, single-arm, dose escalation and expansion study designed to evaluate safety and antineoplastic activity of avapritinib, a selective, potent inhibitor of KIT and PDGFRA, in patients with unresectable or metastatic GIST.Materials and methodsEligible patients were 18 years or older with histologically or cytologically confirmed unresectable GIST and Eastern Cooperative Oncology Group performance status ≤2 and initiated avapritinib at 300 mg or 400 mg once daily. Primary endpoints were safety in patients who initiated avapritinib at 300 mg or 400 mg once daily and overall response rate (ORR) in patients in the safety population with three or more previous lines of TKI therapy.ResultsAs of November 16, 2018, in the safety population (n = 204), the most common adverse events (AEs) were nausea (131 [64%]), fatigue (113 [55%]), anemia (102 [50%]), cognitive effects (84 [41%]), and periorbital edema (83 [41%]); 17 (8%) patients discontinued due to treatment-related AEs, most frequently confusion, encephalopathy, and fatigue. ORR in response-evaluable patients with GIST harboring KIT or non-D842V PDGFRA mutations and with at least three prior therapies (n = 103) was 17% (95% confidence interval [CI], 10-25). Median duration of response was 10.2 months (95% CI, 7.2-10.2), and median progression-free survival was 3.7 months (95% CI, 2.8-4.6).ConclusionAvapritinib has manageable toxicity with meaningful clinical activity as fourth-line or later treatment in some patients with GIST with KIT or PDGFRA mutations.Implications for practiceIn the NAVIGATOR trial, avapritinib, an inhibitor of KIT and platelet-derived growth factor receptor A tyrosine kinases, provided durable responses in a proportion of patients with advanced gastrointestinal stromal tumors (GIST) who had received three or more prior therapies. Avapritinib had a tolerable safety profile, with cognitive adverse events manageable with dose interruptions and modification in most cases. These findings indicate that avapritinib can elicit durable treatment responses in some patients with heavily pretreated GIST, for whom limited treatment options exist.

Dataset Information

Identification of Wee1 as a target in combination with avapritinib for gastrointestinal stromal tumor treatment.

Publications

Identification of Wee1 as a target in combination with avapritinib for gastrointestinal stromal tumor treatment.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets