Selective type II TRK inhibitors overcome xDFG mutation mediated acquired resistance to the second-generation inhibitors selitrectinib and repotrectinib

Xiang, Shuang; Lu, Xiaoyun

doi:10.1016/j.apsb.2023.11.010

Cited by 9 publications

(3 citation statements)

References 124 publications

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“…To overcome secondary resistance mechanisms, ongoing clinical evaluations are assessing the efficacy of additional second-generation TRK inhibitors, including repotrectinib and taletrectinib ( 125 ).…”

Section: Other Potential Treatment Targets For Personalized Therapymentioning

confidence: 99%

Navigating through novelties concerning mCRC treatment—the role of immunotherapy, chemotherapy, and targeted therapy in mCRC

Zheng,

Włodarczyk,

Węgiel

et al. 2024

Front. Surg.

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Over the course of nearly six decades since the inception of initial trials involving 5-FU in the treatment of mCRC (metastatic colorectal cancer), our progressive comprehension of the pathophysiology, genetics, and surgical techniques related to mCRC has paved the way for the introduction of novel therapeutic modalities. These advancements not only have augmented the overall survival but have also positively impacted the quality of life (QoL) for affected individuals. Despite the remarkable progress made in the last two decades in the development of chemotherapy, immunotherapy, and target therapies, mCRC remains an incurable disease, with a 5-year survival rate of 14%. In this comprehensive review, our primary goal is to present an overview of mCRC treatment methods following the latest guidelines provided by the National Comprehensive Cancer Network (NCCN), the American Society of Clinical Oncology (ASCO), and the American Society of Colon and Rectal Surgeons (ASCRS). Emphasis has been placed on outlining treatment approaches encompassing chemotherapy, immunotherapy, targeted therapy, and surgery's role in managing mCRC. Furthermore, our review delves into prospective avenues for developing new therapies, offering a glimpse into the future of alternative pathways that hold potential for advancing the field.

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Section: Other Potential Treatment Targets For Personalized Therapymentioning

confidence: 99%

Navigating through novelties concerning mCRC treatment—the role of immunotherapy, chemotherapy, and targeted therapy in mCRC

Zheng,

Włodarczyk,

Węgiel

et al. 2024

Front. Surg.

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“…The median DOR for the NTRK fusion subgroups to larotrectinib was 8.3 months, and for entrectinib, it was 10.5 months [87]. This is believed to be associated with point mutations in the kinase domain of TRK, including solvent front mutations, gatekeeper mutations, and xDFG motif mutations, such as TRKA G667C/A/S, TRKB G709C/A/S, and TRKC G696C/A/S, as well as the aberrant activation of bypass signaling pathways in TRK, such as acquired BRAF V600E and KRAS G12D mutations, and MET amplification, leading to MAPK pathway activation [87,88]. To overcome acquired resistance mutations, selitrectinib and repotrectinib are two representative second-generation TRK inhibitors.…”

Section: Tropomyosin Receptor Kinase (Trk)mentioning

confidence: 99%

Kinase Inhibitors and Kinase-Targeted Cancer Therapies: Recent Advances and Future Perspectives

Li,

Gong,

Zhou

et al. 2024

IJMS

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Over 120 small-molecule kinase inhibitors (SMKIs) have been approved worldwide for treating various diseases, with nearly 70 FDA approvals specifically for cancer treatment, focusing on targets like the epidermal growth factor receptor (EGFR) family. Kinase-targeted strategies encompass monoclonal antibodies and their derivatives, such as nanobodies and peptides, along with innovative approaches like the use of kinase degraders and protein kinase interaction inhibitors, which have recently demonstrated clinical progress and potential in overcoming resistance. Nevertheless, kinase-targeted strategies encounter significant hurdles, including drug resistance, which greatly impacts the clinical benefits for cancer patients, as well as concerning toxicity when combined with immunotherapy, which restricts the full utilization of current treatment modalities. Despite these challenges, the development of kinase inhibitors remains highly promising. The extensively studied tyrosine kinase family has 70% of its targets in various stages of development, while 30% of the kinase family remains inadequately explored. Computational technologies play a vital role in accelerating the development of novel kinase inhibitors and repurposing existing drugs. Recent FDA-approved SMKIs underscore the importance of blood–brain barrier permeability for long-term patient benefits. This review provides a comprehensive summary of recent FDA-approved SMKIs based on their mechanisms of action and targets. We summarize the latest developments in potential new targets and explore emerging kinase inhibition strategies from a clinical perspective. Lastly, we outline current obstacles and future prospects in kinase inhibition.

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“…Despite the rarity of these fusions, TRK inhibitors are emerging as promising therapeutic options. This promise stems from their broad efficacy across various cancer types of any organ, their ability to cross the blood‒brain barrier (BBB) effectively, and the ongoing improvement of second-generation inhibitors designed to overcome resistance [ 7 , 16 , 22 , 32 ].…”

Section: Introductionmentioning

confidence: 99%

NTRK-fused central nervous system tumours: clinicopathological and genetic insights and response to TRK inhibitors

Kim,

Park,

Kim

et al. 2024

acta neuropathol commun

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Background Neurotrophic tropomyosin receptor kinase (NTRK) gene fusions are found in 1% of gliomas across children and adults. TRK inhibitors are promising therapeutic agents for NTRK-fused gliomas because they are tissue agnostic and cross the blood–brain barrier (BBB). Methods We investigated twelve NGS-verified NTRK-fused gliomas from a single institute, Seoul National University Hospital. Results The patient cohort included six children (aged 1–15 years) and six adults (aged 27–72 years). NTRK2 fusions were found in ten cerebral diffuse low-grade and high-grade gliomas (DLGGs and DHGGs, respectively), and NTRK1 fusions were found in one cerebral desmoplastic infantile ganglioglioma and one spinal DHGG. In this series, the fusion partners of NTRK2 were HOOK3, KIF5A, GKAP1, LHFPL3, SLMAP, ZBTB43, SPECC1L, FKBP15, KANK1, and BCR, while the NTRK1 fusion partners were TPR and TPM3. DLGGs tended to harbour only an NTRK fusion, while DHGGs exhibited further genetic alterations, such as TERT promoter/TP53/PTEN mutation, CDKN2A/2B homozygous deletion, PDGFRA/KIT/MDM4/AKT3 amplification, or multiple chromosomal copy number aberrations. Four patients received adjuvant TRK inhibitor therapy (larotrectinib, repotrectinib, or entrectinib), among which three also received chemotherapy (n = 2) or proton therapy (n = 1). The treatment outcomes for patients receiving TRK inhibitors varied: one child who received larotrectinib for residual DLGG maintained stable disease. In contrast, another child with DHGG in the spinal cord experienced multiple instances of tumour recurrence. Despite treatment with larotrectinib, ultimately, the child died as a result of tumour progression. An adult patient with glioblastoma (GBM) treated with entrectinib also experienced tumour progression and eventually died. However, there was a successful outcome for a paediatric patient with DHGG who, after a second gross total tumour removal followed by repotrectinib treatment, showed no evidence of disease. This patient had previously experienced relapse after the initial surgery and underwent autologous peripheral blood stem cell therapy with carboplatin/thiotepa and proton therapy. Conclusions Our study clarifies the distinct differences in the pathology and TRK inhibitor response between LGG and HGG with NTRK fusions.

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Selective type II TRK inhibitors overcome xDFG mutation mediated acquired resistance to the second-generation inhibitors selitrectinib and repotrectinib

Cited by 9 publications

References 124 publications

Navigating through novelties concerning mCRC treatment—the role of immunotherapy, chemotherapy, and targeted therapy in mCRC

Navigating through novelties concerning mCRC treatment—the role of immunotherapy, chemotherapy, and targeted therapy in mCRC

Kinase Inhibitors and Kinase-Targeted Cancer Therapies: Recent Advances and Future Perspectives

NTRK-fused central nervous system tumours: clinicopathological and genetic insights and response to TRK inhibitors

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