Targets for Systemic Mastocytosis

Systemic Mastocytosis (SM) is a clonal mast cell disease characterized by the proliferation and accumulation of abnormal mast cells in various tissues, most notably the bone marrow, skin, liver, spleen, and gastrointestinal tract. Understanding the molecular targets involved in SM pathogenesis is critical for elucidating disease mechanisms, identifying actionable therapeutic interventions, and promoting the development of targeted therapies. The most central and well-validated disease driver is activating mutations in KIT, particularly KIT D816V, which leads to constitutive activation of the KIT receptor tyrosine kinase and uncontrolled mast cell proliferation and survival. Additional tyrosine kinases (such as PDGFRA, PDGFRB, FGFR3, and FLT3), anti-apoptotic regulators (BCL2, BCL2L1), and signaling intermediates (LYN, BTK, MTOR) may play supporting or modulating roles in mast cell biology and resistance mechanisms. Collectively, these targets define the oncogenic signaling landscape of SM and provide a framework for the development of small molecule inhibitors, antibody therapies, and combination regimens. By focusing on these validated and mechanistically relevant targets, research and drug development can be more precisely tailored to disrupt key pathogenic pathways, improve patient outcomes, and overcome resistance to therapy.

Receptor Tyrosine Kinases And Signaling Pathways

This category includes receptor tyrosine kinases and intracellular signaling molecules that are directly implicated in the pathogenesis of Systemic Mastocytosis. The most critical member is KIT (KIT), which harbors activating mutations in the majority of SM cases and drives mast cell proliferation, survival, and accumulation. Additional kinases such as PDGFRA (platelet derived growth factor receptor alpha), PDGFRB (platelet derived growth factor receptor beta), FGFR3 (fibroblast growth factor receptor 3), FLT3 (fms related receptor tyrosine kinase 3), LYN (LYN proto-oncogene, Src family tyrosine kinase), and MTOR (mechanistic target of rapamycin kinase) have been implicated in SM either as co-drivers, resistance mediators, or modulators of mast cell function. These targets are central to the aberrant growth factor signaling and downstream pathway activation that characterize SM and are the focus of current and emerging targeted therapies.

KIT proto-oncogene, receptor tyrosine kinase (KIT)

KIT proto-oncogene, receptor tyrosine kinase (KIT) is a type III receptor tyrosine kinase with an extracellular ligand-binding domain, a transmembrane helix, and a split cytoplasmic kinase domain. The KIT protein is encoded by the KIT gene (Entrez: 3815, KEGG: 3815, UniProt: P10721). Ligand binding (stem cell factor, SCF) induces dimerization and autophosphorylation, activating downstream signaling pathways including MAPK, PI3K/AKT, and STAT. In Systemic Mastocytosis, the majority of cases harbor activating mutations in KIT, most commonly D816V, which results in ligand-independent constitutive activation of the kinase. This drives uncontrolled mast cell proliferation, survival, and resistance to apoptosis. KIT D816V is the principal molecular driver of SM and is used as a diagnostic and prognostic biomarker. Targeted inhibitors such as midostaurin and avapritinib have demonstrated clinical efficacy in SM patients with KIT mutations, leading to significant reductions in mast cell burden and symptom improvement. KIT is the most clinically validated and actionable target in SM.

platelet derived growth factor receptor alpha (PDGFRA)

Platelet derived growth factor receptor alpha (PDGFRA) is a class III receptor tyrosine kinase structurally related to KIT, with extracellular immunoglobulin-like domains and a cytoplasmic kinase domain (Entrez: 5156, KEGG: 5156, UniProt: P16234). PDGFRA mutations are rare in SM but have been reported in some cases, particularly those with overlapping myeloid neoplasms or SM with eosinophilia. PDGFRA activation leads to signaling through PI3K/AKT, RAS/MAPK, and STAT pathways, contributing to cell proliferation and survival. While not a primary driver in most SM, PDGFRA mutations may represent alternative oncogenic mechanisms and are therapeutically targetable with tyrosine kinase inhibitors such as imatinib in KIT D816V-negative cases.

platelet derived growth factor receptor beta (PDGFRB)

Platelet derived growth factor receptor beta (PDGFRB) is another class III receptor tyrosine kinase (Entrez: 5159, KEGG: 5159, UniProt: P09619). It is structurally similar to KIT and PDGFRA, and activates similar downstream signaling cascades. PDGFRB mutations or rearrangements are rare but have been identified in some patients with myeloid neoplasms and mast cell disease. Like PDGFRA, PDGFRB is a potential therapeutic target in SM patients lacking KIT mutations, and its activation may contribute to mast cell proliferation and disease progression.

fibroblast growth factor receptor 3 (FGFR3)

Fibroblast growth factor receptor 3 (FGFR3) is a transmembrane receptor tyrosine kinase (Entrez: 2261, KEGG: 2261, UniProt: P22607) with three extracellular immunoglobulin-like domains, a single transmembrane helix, and an intracellular tyrosine kinase domain. FGFR3 mutations have been implicated in various cancers and in rare cases of SM, particularly those with associated myeloid neoplasms. FGFR3 activation stimulates MAPK, PI3K/AKT, and STAT pathways, supporting cell growth and survival. While not a primary driver in most SM, FGFR3 may contribute to disease progression in select cases and is a candidate for targeted inhibition.

fms related receptor tyrosine kinase 3 (FLT3)

Fms related receptor tyrosine kinase 3 (FLT3) is a class III receptor tyrosine kinase (Entrez: 2322, KEGG: 2322, UniProt: P36888) involved in hematopoietic stem cell development. FLT3 mutations are rare in SM but may occur in cases with associated myeloid neoplasms. FLT3 activation leads to PI3K/AKT and MAPK signaling, promoting proliferation and survival. FLT3 inhibitors are being explored in myeloid neoplasms and may have relevance in select SM patients with FLT3 involvement.

LYN proto-oncogene, Src family tyrosine kinase (LYN)

LYN proto-oncogene, Src family tyrosine kinase (LYN) is a non-receptor tyrosine kinase (Entrez: 4067, KEGG: 4067, UniProt: P07948) with SH3, SH2, and kinase domains. LYN is involved in transducing signals downstream of KIT and FcεRI in mast cells, modulating activation, proliferation, and survival. Aberrant LYN activation has been implicated in mast cell neoplasms, and LYN may contribute to resistance mechanisms in SM. Inhibitors of Src family kinases are under investigation for their potential to modulate mast cell signaling.

mechanistic target of rapamycin kinase (MTOR)

Mechanistic target of rapamycin kinase (MTOR) is a serine/threonine kinase (Entrez: 2475, KEGG: 2475, UniProt: P42345) that integrates signals from growth factors, nutrients, and energy status to regulate cell growth, proliferation, and survival. MTOR is a downstream effector of KIT and other tyrosine kinases in mast cells. Hyperactivation of MTOR signaling has been observed in SM, contributing to increased mast cell proliferation and resistance to apoptosis. MTOR inhibitors (e.g., everolimus) have shown preclinical activity in mast cell neoplasms and may be considered in refractory or advanced SM.

Apoptosis And Cell Survival Regulators

This category includes anti-apoptotic proteins that are upregulated in neoplastic mast cells in Systemic Mastocytosis. BCL2 (BCL2 apoptosis regulator) and BCL2L1 (BCL2 like 1) are key members of the BCL2 family and function to inhibit programmed cell death, thereby promoting mast cell survival and contributing to disease persistence. Their overexpression is associated with resistance to apoptosis-inducing therapies and may be a mechanism of resistance to KIT inhibitors. Targeting these proteins can sensitize mast cells to apoptosis and represents a promising therapeutic strategy.

BCL2 apoptosis regulator (BCL2)

BCL2 apoptosis regulator (BCL2) is an integral mitochondrial membrane protein (Entrez: 596, KEGG: 596, UniProt: P10415) with four BCL2 homology (BH) domains. BCL2 inhibits the intrinsic (mitochondrial) apoptosis pathway by binding and sequestering pro-apoptotic proteins (e.g., BAX, BAK). In Systemic Mastocytosis, BCL2 is overexpressed in neoplastic mast cells, contributing to their survival and resistance to apoptosis. Increased BCL2 expression is associated with aggressive disease and poor response to therapy. BCL2 inhibitors (e.g., venetoclax) are being explored as adjunct therapies to overcome resistance and induce mast cell apoptosis.

BCL2 like 1 (BCL2L1)

BCL2 like 1 (BCL2L1), also known as BCL-XL, is a mitochondrial membrane protein (Entrez: 598, KEGG: 598, UniProt: Q07817) with anti-apoptotic function. It shares structural homology with BCL2 and contains BH domains that enable binding to pro-apoptotic family members. Overexpression of BCL2L1 in mast cells enhances survival and contributes to resistance against apoptosis-inducing agents, including KIT inhibitors. Targeting BCL2L1, alone or in combination with BCL2 inhibition, may sensitize neoplastic mast cells to apoptosis and improve therapeutic outcomes in SM.