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Ref Type

PMID

(33212994)

Authors

Fornasarig M, Gasparotto D, Foltran L, Campigotto M, Lombardi S, Del Savio E, Buonadonna A, Puglisi F, Sulfaro S, Canzonieri V, Cannizzaro R, Maestro R

Title

A Novel Kindred with Familial Gastrointestinal Stromal Tumors Caused by a Rare KIT Germline Mutation (N655K): Clinico-Pathological Presentation and TKI Sensitivity.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of personalized medicine	10	4	2020 Nov 17		J Pers Med

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Abstract Text

Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the gastrointestinal tract, are characterized by activating mutations in KIT or PDGFRA genes. The vast majority of GISTs are sporadic, but rare hereditary forms have been reported, often featuring multifocality and younger age of onset. We here report the identification of a novel kindred affected by familial GIST caused by a KIT germline mutation in exon 13 (N655K). No family affected by hereditary GIST due to this KIT variant has been reported in literature so far. We were able to track the mutation in three members of the family (proband, mother, and second-degree cousin), all affected by multiple GISTs. Due to its rarity, the N655K variant is poorly characterized. We conducted in vitro drug sensitivity assays that indicated that most tyrosine kinase inhibitors (TKIs) currently included in the therapeutic armamentarium for GISTs have a limited inhibitory activity toward this mutation. However, when compared to a classical imatinib-resistant KIT mutation (T670I), N655K was slightly more sensitive to imatinib, and encouraging responses were observed with last-generation TKIs.

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Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
KIT N655K	gastrointestinal stromal tumor	predicted - sensitive	Imatinib	Case Reports/Case Series	Actionable	In a clinical case study, a patient with gastrointestinal stromal tumor (GIST) harboring a germline KIT N655K mutation, associated with hereditary GIST syndrome, demonstrated slow disease progression for 12 months while on treatment with Gleevec (imatinib) at 400mg/d, and upon disease progression following surgery and 15 months of Sutent (sunitinib) treatment, was rechallenged with Gleevec (imatinib) at 800mg/d and remained stable for a further 9 months (PMID: 33212994).	33212994
KIT N655K	Advanced Solid Tumor	decreased response	Cabozantinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing KIT N655K demonstrated a reduced response to Cometriq (Cabometyx, cabozantinib) treatment compared to cells expressing KIT T670I in culture (PMID: 33212994).	33212994
KIT N655K	Advanced Solid Tumor	decreased response	Sunitinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing KIT N655K demonstrated a reduced response to Sutent (sunitinib) treatment compared to cells expressing KIT T670I in culture (PMID: 33212994).	33212994
KIT N655K	Advanced Solid Tumor	predicted - sensitive	Ripretinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing KIT N655K demonstrated some sensitivity to Qinlock (ripretinib) treatment in culture, but were less sensitive than cells expressing KIT W557_K558del (PMID: 33212994).	33212994
KIT N655K	Advanced Solid Tumor	predicted - sensitive	Imatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing KIT N655K demonstrated some sensitivity to Gleevec (imatinib) treatment in culture, resulting in reduced cell viability at high treatment dosages (PMID: 33212994).	33212994
KIT N655K	Advanced Solid Tumor	predicted - sensitive	Avapritinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing KIT N655K demonstrated some sensitivity to Ayvakit (avapritinib) in culture, but were less sensitive than cells expressing KIT W557_K558del (PMID: 33212994).	33212994
KIT N655K	Advanced Solid Tumor	decreased response	Regorafenib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing KIT N655K demonstrated a reduced response to Stivarga (regorafenib) treatment compared to cells expressing KIT T670I in culture (PMID: 33212994).	33212994
KIT T670I	Advanced Solid Tumor	sensitive	Regorafenib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing KIT T670I demonstrated sensitivity to Stivarga (regorafenib) treatment in culture, resulting in reduced cell viability (PMID: 33212994).	33212994
KIT T670I	Advanced Solid Tumor	sensitive	Sunitinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing KIT T670I demonstrated sensitivity to Sutent (sunitinib) treatment in culture, resulting in reduced cell viability (PMID: 33212994).	33212994
KIT T670I	Advanced Solid Tumor	sensitive	Cabozantinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing KIT T670I demonstrated sensitivity to Cometriq (Cabometyx, cabozantinib) treatment in culture, resulting in reduced cell viability (PMID: 33212994).	33212994
KIT T670I	Advanced Solid Tumor	resistant	Imatinib	Preclinical - Cell culture	Actionable	In a preclinical study, transformed cells expressing KIT T670I were resistant to treatment with Gleevec (imatinib) in culture (PMID: 33212994).	33212994
KIT W557_K558del	Advanced Solid Tumor	sensitive	Cabozantinib	Preclinical - Cell culture	Actionable	In a preclinical study, Cometriq (Cabometyx, cabozantinib) treatment resulted in decreased viability of transformed cells expressing KIT W557_K558del in culture (PMID: 33212994).	33212994

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