Secondary KIT mutations: the GIST of drug resistance and sensitivity

Napolitano, Andrea; Vincenzi, Bruno

doi:10.1038/s41416-019-0388-7

Cited by 40 publications

(35 citation statements)

References 10 publications

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“…TKIs are the standard of care in the primary treatment of GIST, and imatinib is the most commonly used compound (Casali et al , 2018). The resistance toward TKIs in GIST is mainly related to secondary mutations of KIT (Li & Raut, 2019; Napolitano & Vincenzi, 2019), but can also be triggered by PDGFRA mutations (Lim et al , 2008; Kalfusova et al , 2019).…”

Section: Epidemiology Of Sarcomamentioning

confidence: 99%

Sarcoma treatment in the era of molecular medicine

et al. 2020

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Sarcomas are heterogeneous and clinically challenging soft tissue and bone cancers. Although constituting only 1% of all human malignancies, sarcomas represent the second most common type of solid tumors in children and adolescents and comprise an important group of secondary malignancies. More than 100 histological subtypes have been characterized to date, and many more are being discovered due to molecular profiling. Owing to their mostly aggressive biological behavior, relative rarity, and occurrence at virtually every anatomical site, many sarcoma subtypes are in particular difficult‐to‐treat categories. Current multimodal treatment concepts combine surgery, polychemotherapy (with/without local hyperthermia), irradiation, immunotherapy, and/or targeted therapeutics. Recent scientific advancements have enabled a more precise molecular characterization of sarcoma subtypes and revealed novel therapeutic targets and prognostic/predictive biomarkers. This review aims at providing a comprehensive overview of the latest advances in the molecular biology of sarcomas and their effects on clinical oncology; it is meant for a broad readership ranging from novices to experts in the field of sarcoma.

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Section: Epidemiology Of Sarcomamentioning

confidence: 99%

Sarcoma treatment in the era of molecular medicine

et al. 2020

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“…TruSeq Custom Amplicon (TSCA) low input sequencing panel, covering the entire coding region of NF1, SDHA, SDHB, SDHC, SDHD, and selected exons of KIT (exons 8,9,11,13,14,17,18), PDGFRA (exons 12,14,18), BRAF (exons 11 and 15), NRAS (exons 2 and 3), and KRAS (exons 2, 3 and 4), was designed with Design Studio software (Illumina). All KIT and PDGFRA exons target of primary or secondary mutations indicated in the most recent guidelines on GIST molecular diagnostics were included in this panel (19,20). BRAF, NRAS, and KRAS recurrent hotspot mutations were covered.…”

Section: Targeted Deep Sequencingmentioning

confidence: 99%

Targeted Deep Sequencing Uncovers Cryptic KIT Mutations in KIT/PDGFRA/SDH/RAS-P Wild-Type GIST

et al. 2020

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Background: Gastrointestinal stromal tumors (GIST) are known to carry oncogenic KIT or PDGFRA mutations, or less commonly SDH or NF1 gene inactivation, with very rare cases harboring mutant BRAF or RAS alleles. Approximately 10% of GISTs are devoid of any of such mutations and are characterized by very limited therapeutic opportunities and poor response to standard treatments. Methods: Twenty-six sporadic KIT/PDGFRA/SDH/RAS-pathway wild type GIST were profiled for the molecular status of genes frequently altered in GIST by a targeted next generation sequencing (NGS) approach. Molecular findings were validated by alternative amplicon-based targeted sequencing, immunohistochemistry, gene expression profiling and Sanger sequencing. Results: Three patients harboring NF1 inactivating mutations were identified and excluded from further analysis. Intriguingly, five patients carried cryptic KIT alterations, mainly represented by low-allele-fraction mutations (12-16% allele ratio). These mutations were confirmed by another targeted NGS approaches and supported by CD117 immuno-staining, gene expression profiling, Sanger sequencing, with peak signals at the level of background noise, and by the patients' clinical course assessment. Conclusion: This study indicates that ∼20% patients diagnosed with a KIT/PDGFRA/SDH/RAS-pathway wild-type GIST are bona-fide carriers of pathogenic KIT mutations, thus expected to be eligible for and responsive to the various therapeutic lines of TK-inhibitors in use for KIT/PDGFRA-mutant GIST. The centralization for a second level molecular analysis of GIST samples diagnosed as wild-type for KIT and PDGFRA is once again strongly recommended.

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“…GIST patients with KIT exon 9 mutations had a significantly worse prognosis compared to those with KIT exon 11 mutations [ 123 ], who also exhibited worse response to imatinib treatment [ 125 ]. Other TKIs, such as sunitinib and regorafenib, have complementary activity in that sunitinib targets the ATP-binding pocket to inhibit imatinib-resistance mutations, whereas regorafenib primarily targets the activation loop to achieve similar effects [ 126 ]. Once imatinib resistance emerges, sunitinib and regorafenib as second- and third-line molecular targeted therapies, could provide clinical benefit in a short-term [ 127 , 128 , 129 ].…”

Section: Challenges and Future Directionsmentioning

confidence: 99%

Therapeutic Potential of PI3K/AKT/mTOR Pathway in Gastrointestinal Stromal Tumors: Rationale and Progress

Duan

Haybaeck

Yang

2020

Cancers

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Gastrointestinal stromal tumor (GIST) originates from interstitial cells of Cajal (ICCs) in the myenteric plexus of the gastrointestinal tract. Most GISTs arise due to mutations of KIT and PDGFRA gene activation, encoding the receptor tyrosine kinase (RTK). The clinical use of the RTK inhibitor imatinib has significantly improved the management of GIST patients; however, imatinib resistance remains a challenge. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway is a critical survival pathway for cell proliferation, apoptosis, autophagy and translation in neoplasms. Constitutive autophosphorylation of RTKs has an impact on the activation of the PI3K/AKT/mTOR pathway. In several preclinical and early-stage clinical trials PI3K/AKT/mTOR signaling inhibition has been considered as a promising targeted therapy strategy for GISTs. Various inhibitory drugs targeting different parts of the PI3K/AKT/mTOR pathway are currently being investigated in phase I and phase II clinical trials. This review highlights the progress for PI3K/AKT/mTOR-dependent mechanisms in GISTs, and explores the relationship between mTOR downstream signals, in particular, eukaryotic initiation factors (eIFs) and the development of GISTs, which may be instrumental for identifying novel therapeutic targets.

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Secondary KIT mutations: the GIST of drug resistance and sensitivity

Cited by 40 publications

References 10 publications

Sarcoma treatment in the era of molecular medicine

Sarcoma treatment in the era of molecular medicine

Targeted Deep Sequencing Uncovers Cryptic KIT Mutations in KIT/PDGFRA/SDH/RAS-P Wild-Type GIST

Therapeutic Potential of PI3K/AKT/mTOR Pathway in Gastrointestinal Stromal Tumors: Rationale and Progress

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