Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours

Liu, Juan; Gao, Jingjing; Wang, Aoli; Jiang, Zongru; Qi, Shuang; Zhou, Qi; Liu, Feiyang; Yu, Kewei; Cao, Jiangyan; Cheng, Chen; Hu, Changwei; Wu, Hong; Wang, Li; Wang, Qianqian; Liu, Qingsong; Liu, Jing

doi:10.1002/1878-0261.13199

Cited by 7 publications

(5 citation statements)

References 49 publications

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“…The clinical challenge posed by KIT AP/AL mutations is underscored by the kinase inhibitor screens herein, in which few drugs were active against AP/AL mutants. We observed modest anti-AP/AL activity for sunitinib and the structurally related nintedanib, which was recently reported to be a KIT inhibitor 32 and is approved for subtypes of non–small-cell lung cancer. 33 Crenolanib and avapritinib, developed and approved, respectively, for treatment of PDGFRA D842V -mutant GISTs, also showed modest activity against AP/AL mutations.…”

Section: Discussionmentioning

confidence: 71%

“…The clinical challenge posed by KIT AP/AL mutations is underscored by the kinase inhibitor screens herein, in which few drugs were active against AP/AL mutants. We observed modest anti-AP/AL activity for sunitinib and the structurally related nintedanib, which was recently reported to be a KIT inhibitor 32 and is approved for subtypes of non-small-cell lung cancer. 33 T1-a-D842V+V658A >1000 >1000 >1000 >1000 >1000 >1000 >1000 >1000 >1000 T1-a-D842V+T674R >1000 >1000 >1000 >1000 >1000 >1000 >1000 >1000 >1000 >1000 >1000 >1000 >1000 >1000 >1000 >1000 >1000 >1000 treatment of PDGFRA D842V -mutant GISTs, also showed modest activity against AP/AL mutations.…”

Section: Ripretinib and Sunitinib Exhibit Reciprocal Activity Against...mentioning

confidence: 71%

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KIT ATP-Binding Pocket/Activation Loop Mutations in GI Stromal Tumor: Emerging Mechanisms of Kinase Inhibitor Escape

Mühlenberg,

Falkenhorst,

Schulz

et al. 2024

JCO

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PURPOSE Imatinib resistance in GI stromal tumors (GISTs) is primarily caused by secondary KIT mutations, and clonal heterogeneity of these secondary mutations represents a major treatment obstacle. KIT inhibitors used after imatinib have clinical activity, albeit with limited benefit. Ripretinib is a potent inhibitor of secondary KIT mutations in the activation loop (AL). However, clinical benefit in fourth line remains limited and the molecular mechanisms of ripretinib resistance are largely unknown. PATIENTS AND METHODS Progressing lesions of 25 patients with GISTs refractory to ripretinib were sequenced for KIT resistance mutations. Resistant genotypes were validated and characterized using novel cell line models and in silico modeling. RESULTS GISTs progressing on ripretinib were enriched for secondary mutations in the ATP-binding pocket (AP), which frequently occur in cis with preexisting AL mutations, resulting in highly resistant AP/AL genotypes. AP/AL mutations were rarely observed in a cohort of progressing GIST samples from the preripretinib era but represented 50% of secondary KIT mutations in patients with tumors resistant to ripretinib. In GIST cell lines harboring secondary KIT AL mutations, the sole genomic escape mechanisms during ripretinib drug selection were AP/AL mutations. Ripretinib and sunitinib synergize against mixed clones with secondary AP or AL mutants but do not suppress clones with AP/AL genotypes. CONCLUSION Our findings underscore that KIT remains the central oncogenic driver even in late lines of GIST therapy. KIT-inhibitor combinations may suppress resistance because of secondary KIT mutations. However, the emergence of KIT AP/AL mutations after ripretinib treatment calls for new strategies in the development of next-generation KIT inhibitors.

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Section: Discussionmentioning

confidence: 71%

“…The clinical challenge posed by KIT AP/AL mutations is underscored by the kinase inhibitor screens herein, in which few drugs were active against AP/AL mutants. We observed modest anti-AP/AL activity for sunitinib and the structurally related nintedanib, which was recently reported to be a KIT inhibitor 32 and is approved for subtypes of non-small-cell lung cancer. 33 T1-a-D842V+V658A >1000 >1000 >1000 >1000 >1000 >1000 >1000 >1000 >1000 T1-a-D842V+T674R >1000 >1000 >1000 >1000 >1000 >1000 >1000 >1000 >1000 >1000 >1000 >1000 >1000 >1000 >1000 >1000 >1000 >1000 treatment of PDGFRA D842V -mutant GISTs, also showed modest activity against AP/AL mutations.…”

Section: Ripretinib and Sunitinib Exhibit Reciprocal Activity Against...mentioning

confidence: 71%

KIT ATP-Binding Pocket/Activation Loop Mutations in GI Stromal Tumor: Emerging Mechanisms of Kinase Inhibitor Escape

Mühlenberg,

Falkenhorst,

Schulz

et al. 2024

JCO

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“…RSL3 was dissolved in DMSO, diluted in corn oil (#HY-Y1888, MCE), and then intraperitoneally injected into mice with IM (100 mg/kg) or RSL3 (10 mg/kg) every 3 days. The dosages of IM and RSL3 were determined based on previous studies [ 24 , 25 ] and our own preliminary experimental results. Tumor sizes were measured every 3 days, and tumor volumes were calculated as follows: 0.5×length×width 2 .…”

Section: Methodsmentioning

confidence: 99%

Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination

Sun,

Zhang,

Lin

et al. 2023

Cell Death Dis

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Imatinib (IM) has significantly improved the prognosis of gastrointestinal stromal tumor (GIST) patients, but some patients still have primary resistance to IM, and approximately half of patients develop acquired drug resistance within 2 years of treatment, necessitating exploration of new treatment strategies. Targeting ferroptosis as a novel approach to tumor treatment has gained attention. Yet, there is limited research on ferroptosis in GIST, and the underlying mechanism remains unclear. In this study, we revealed that IM increased lipid reactive oxygen species and intracellular Fe2+ levels, and decreased glutathione levels in GIST. This effect could be partially inhibited by Ferrostatin-1. Additionally, knocking down STUB1 and overexpressing GPX4 reversed the IM-induced ferroptosis effect. Moreover, STUB1 was identified as a novel E3 ubiquitin ligase of GPX4, promoting the ubiquitination at site K191 of GPX4. The combination of the GPX4 inhibitor RSL3 and IM synergistically induces ferroptosis, inhibiting GIST proliferation both in vivo and in vitro. Furthermore, STUB1 and GPX4 expression serve as independent prognostic factors for GIST. In conclusion, This study is the first to demonstrate that IM induces ferroptosis by promoting STUB1-mediated GPX4 ubiquitination in GIST, and the combination of RSL3 and IM emerges as a promising therapeutic strategy for GIST.

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“…With the combination of BGJ398 and sunitinib, SDH-GIST patients may get better outcomes [ 102 ]. Nintedanib, first approved by FDA for idiopathic pulmonary fibrosis, overcame not only resistance induced by KIT mutations, but also ERK-reactivation-mediated resistance induced by FGF upregulation [ 43 ]. The combination of FGFR inhibitor PD173074 and IM showed highly synergistic effect in IM-resistant GIST cells [ 213 ].…”

Section: Kit Mutations and Expression In Gistmentioning

confidence: 99%

KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST

Zhou,

Abdihamid,

Tan

et al. 2024

Cell Commun Signal

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Gastrointestinal stromal tumor (GIST) is the most common sarcoma located in gastrointestinal tract and derived from the interstitial cell of Cajal (ICC) lineage. Both ICC and GIST cells highly rely on KIT signal pathway. Clinically, about 80-90% of treatment-naive GIST patients harbor primary KIT mutations, and special KIT-targeted TKI, imatinib (IM) showing dramatic efficacy but resistance invariably occur, 90% of them was due to the second resistance mutations emerging within the KIT gene. Although there are multiple variants of KIT mutant which did not show complete uniform biologic characteristics, most of them have high KIT expression level. Notably, the high expression level of KIT gene is not correlated to its gene amplification. Recently, accumulating evidences strongly indicated that the gene coding, epigenetic regulation, and pre- or post- protein translation of KIT mutants in GIST were quite different from that of wild type (WT) KIT. In this review, we elucidate the biologic mechanism of KIT variants and update the underlying mechanism of the expression of KIT gene, which are exclusively regulated in GIST, providing a promising yet evidence-based therapeutic landscape and possible target for the conquer of IM resistance.

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Nintedanib overcomes drug resistance from upregulation of FGFR signalling and imatinib‐induced KIT mutations in gastrointestinal stromal tumours

Cited by 7 publications

References 49 publications

KIT ATP-Binding Pocket/Activation Loop Mutations in GI Stromal Tumor: Emerging Mechanisms of Kinase Inhibitor Escape

KIT ATP-Binding Pocket/Activation Loop Mutations in GI Stromal Tumor: Emerging Mechanisms of Kinase Inhibitor Escape

Imatinib induces ferroptosis in gastrointestinal stromal tumors by promoting STUB1-mediated GPX4 ubiquitination

KIT mutations and expression: current knowledge and new insights for overcoming IM resistance in GIST

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