Methods of identifying and treating individuals exhibiting mutant kit protein
Inventors
Lee, Francis Y. • Heinrich, Michael C.
Assignees
Bristol Myers Squibb Co • Oregon Health and Science University • US Department of Veterans Affairs
Publication Number
US-8247419-B2
Publication Date
2012-08-21
Expiration Date
2026-06-09
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Abstract
The invention described herein relates to methods of identifying and treating individuals with protein tyrosine kinase associated disorders that have, or may, become resistant to treatment with a kinase inhibitor such as imatinib due to a gain-of-function mutation in KIT tyrosine kinase.
Core Innovation
The invention relates to methods of identifying and treating individuals with protein tyrosine kinase-associated disorders that have, or may become, resistant to treatment with a kinase inhibitor such as imatinib due to a gain-of-function mutation in KIT tyrosine kinase. Specifically, the invention focuses on mutant KIT proteins and provides diagnostic and therapeutic methods and compositions useful in managing disorders involving cells that express such mutant KIT proteins, including cancers and systemic mastocytosis.
The problem addressed arises because imatinib, a potent KIT tyrosine kinase inhibitor, is effective against wild-type KIT and certain juxtamembrane domain (JM) mutant KIT isoforms but fails to inhibit many mutant KIT isoforms that are resistant to clinically achievable doses of imatinib. Notably, imatinib binds only the inactive or closed conformation of KIT. Mutations in the activation loop (AL) domain, such as those at amino acid position 816 (including D816V, D816Y, D816F, and D816H), not only activate kinase activity but also stabilize the AL in an open conformation that does not permit productive imatinib binding, resulting in imatinib resistance in diseases like acute myeloid leukemia, systemic mastocytosis, seminoma, and imatinib-resistant gastrointestinal stromal tumors (GIST). Therefore, there is a need for diagnostic procedures to identify these resistant mutations and for therapeutic agents capable of inhibiting these mutant KIT kinases.
The invention discovers that the compound BMS-354825 (dasatinib), an ATP-competitive dual SRC/ABL inhibitor, potently inhibits the kinase activity of both wild-type and mutant KIT isoforms, including those resistant to imatinib. This compound inhibits the proliferation and induces apoptosis of cells harboring imatinib-resistant KIT mutations. The invention provides methods to identify mutant KIT kinases in biological samples, particularly targeting mutations that confer constitutive activity and imatinib resistance, and tailors treatment accordingly, administering BMS-354825 alone or in combination with other agents such as mTOR inhibitors like rapamycin. It also includes novel allele-specific PCR methods for sensitive detection of such mutations.
Claims Coverage
The claims include one independent claim focusing on a method of treating a mutant KIT kinase disorder using a combination of BMS-354825 and rapamycin, outlining the treatment of disorders associated with specific KIT mutations.
Combination treatment with BMS-354825 and rapamycin for mutant KIT kinase disorders
A method of treating an individual suffering from a mutant KIT kinase disorder by administering a therapeutically effective amount of BMS-354825 (or its pharmaceutically acceptable salts or hydrates) concurrently with a therapeutically effective amount of rapamycin, resulting in synergistic inhibition of the mutant KIT kinase.
Targeting specific mutations at KIT amino acid residue 816
The mutant KIT kinase targeted in the treatment comprises mutations at amino acid residue 816 of KIT kinase, specifically D816Y, D816F, D816V, and D816H.
Treatment of various KIT-associated disorders
The mutant KIT kinase disorders treatable with the combination include mast cell disease, gastrointestinal stromal tumors (GIST), leukemia, and testicular seminoma; more specifically systemic mast cell disorders, mastocytosis, various leukemias including acute lymphocytic, acute lymphoblastic, acute myelogenous, chronic myelogenous, and promyelocytic leukemia.
Treatment of kinase inhibitor-resistant mutations
The mutant KIT kinase in question is at least partially resistant to a first kinase inhibitor, such as a Bcr-Abl kinase inhibitor, including imatinib.
Constitutively active and imatinib-resistant mutant KIT kinase
The method applies to mutant KIT kinases that are constitutively active and/or imatinib-resistant mutations.
Administration modalities
The claims cover administration of BMS-354825 and rapamycin either simultaneously, including as a combined pharmaceutical composition, or sequentially.
The claims broadly cover the therapeutic use of a combination of BMS-354825 and rapamycin to treat mutant KIT kinase disorders characterized by mutations at amino acid 816, including those resistant to other kinase inhibitors like imatinib, with defined administration methods and targeted disease indications.
Stated Advantages
BMS-354825 effectively inhibits both wild-type and mutant KIT kinases, including those resistant to imatinib.
The combination of BMS-354825 with rapamycin demonstrates synergistic inhibitory effects on mutant KIT kinase, enhancing therapeutic efficacy.
Higher potency of BMS-354825 compared to imatinib against activation loop mutant KIT kinases, allowing effective treatment of resistant disorders.
The invention enables tailored treatment regimens based on specific KIT mutations, improving individualized therapy.
Allele-specific PCR methods improve sensitivity and specificity in detecting mutant KIT kinases, facilitating diagnosis and treatment decisions.
Documented Applications
Identification and treatment of protein tyrosine kinase-associated disorders involving mutant KIT kinases, including cancers and systemic mastocytosis.
Treatment of imatinib-resistant KIT mutant-associated diseases such as systemic mast cell disorders, acute myelogenous leukemia, seminoma, and gastrointestinal stromal tumors.
Diagnostic screening of biological samples (e.g., tissue biopsy, blood, bone marrow aspirate) for detecting specific KIT mutations to guide therapy.
Use of BMS-354825 alone or in combinations with other kinase inhibitors, tubulin stabilizing agents, farnesyl transferase inhibitors, and mTOR inhibitors like rapamycin in cancer treatment.
Application of allele-specific PCR assays for sensitive detection of KIT D816V and D816F mutations in clinical specimens, including formalin-fixed and paraffin-embedded tissues.
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