PDGFRA: A Hub in Cellular Signaling and a Therapeutic Target

2. Structural and Functional Basis of PDGFRA

5. Research Progress in PDGFRA-Targeted Drugs

1. Research Background of PDGFR

Platelet-derived growth factor receptors (PDGFRs) belong to the receptor tyrosine kinase (RTK) family and consist of two subtypes: PDGFRA and PDGFRB ^[1,2]. Among them, PDGFRA primarily mediates signals from ligands such as PDGF-AA, PDGF-AB, and PDGF-CC ^[3]. During embryonic development, PDGFRA is widely expressed in mesenchymal cells, fibroblasts, and smooth muscle progenitor cells, playing an important role in cell migration, tissue remodeling, and angiogenesis ^[4].

In pathological states, aberrant PDGFRA signaling is considered a key pathogenic mechanism in various diseases, including tumors, fibrosis, atherosclerosis, and neurological disorders ^[5,6]. Particularly in gastrointestinal stromal tumors (GIST), PDGFRA gene mutations can lead to conformational changes and constitutive activation of the receptor, representing another major driving factor following KIT mutations ^[7].

2. Structural and Functional Basis of PDGFRA

2.1 Structural Characteristics of PDGFRA

The PDGFRA gene is located on chromosome 4q12 and encodes a transmembrane glycoprotein of approximately 1089 amino acids, containing five immunoglobulin-like extracellular domains, a single transmembrane domain, and an intracellular tyrosine kinase domain ^[11]. Among these, the third and fourth domains form the ligand-binding region, while the fifth domain is involved in receptor dimerization ^[12]. Upon receptor activation, its intracellular tyrosine residues are autophosphorylated, providing docking sites for downstream signaling pathways ^[13].

PDGFRA is highly homologous in structure to PDGFRB but differs in ligand specificity and signal transduction. PDGFRA primarily responds to PDGF-AA, PDGF-AB, and PDGF-CC, whereas PDGFRB is more sensitive to PDGF-BB and PDGF-DD ^[14].

Furthermore, PDGFRA can undergo cross-phosphorylation with other receptors such as FGFR and EGFR, forming a complex signaling regulatory network ^[15].

2.2 Ligands and Activation Mechanism of PDGFRA

The PDGF family consists of four polypeptide chains (A, B, C, D), which form five hetero/homologous ligands through dimerization: PDGF-AA, PDGF-BB, PDGF-AB, PDGF-CC, and PDGF-DD ^[16]. These ligands bind to PDGFR subtypes, inducing receptor dimerization and autophosphorylation, thereby activating downstream signaling cascades.

PDGF-AA primarily binds to PDGFRA homodimers (αα), while PDGF-BB can bind to αα, ββ, and αβ complexes ^[17]. PDGF-CC requires proteolytic cleavage for activation under physiological conditions; its binding to PDGFRA promotes cell migration and angiogenesis ^[18].

After receptor activation, multiple intracellular tyrosine residues of PDGFRA (e.g., Y572, Y742, Y988, Y1018) are phosphorylated, binding to molecules such as PI3K, PLCγ, Src, and Shp2, thereby triggering multiple signaling pathways ^[19,20].

2.3 Physiological Functions of PDGFRA

PDGFRA plays a crucial role in tissue development and maintenance. During embryogenesis, it is indispensable for the development of the neural crest, heart, lung, and kidneys ^[21]. Mice lacking PDGFRA exhibit severe developmental defects, including neural tube malformations and impaired angiogenesis ^[22]. In adult tissues, PDGFRA regulates the proliferation and migration of fibroblasts, smooth muscle cells, and hepatic stellate cells ^[23]. Additionally, it participates in wound repair and extracellular matrix deposition ^[24]. Overactivated PDGFRA signaling often leads to excessive cell proliferation and fibrosis, serving as an important pathological basis for various chronic diseases ^[25].

3. PDGFRA Signaling Pathways

Upon activation, PDGFRA regulates cell proliferation, differentiation, migration, and survival through several classic signaling pathways, primarily including PI3K/Akt, Ras/MAPK, JAK/STAT, and PLCγ pathways.

3.1 PI3K/Akt Pathway

The PI3K/Akt pathway is one of the primary survival signals mediated by PDGFRA ^[26]. After receptor activation, PI3K binds to phosphorylated tyrosine residues (Y742) and is activated, subsequently catalyzing the conversion of PIP2 to PIP3, recruiting Akt to the plasma membrane where it is phosphorylated by PDK1 ^[27]. Activated Akt promotes the phosphorylation of downstream molecules such as mTOR, GSK3β, and BAD, thereby enhancing cell survival and metabolic activity ^[28]. In tumor cells, upregulation of the PI3K/Akt signal can inhibit apoptosis and enhance drug resistance ^[29]. Furthermore, PDGFRA-PI3K/Akt signaling is involved in the differentiation of fibroblasts into myofibroblasts, a key step in fibrosis formation ^[30].

3.2 Ras/MAPK Pathway

The Ras/MAPK pathway primarily mediates signals for cell proliferation and migration. Phosphorylated Y988 and Y1018 of PDGFRA recruit the Grb2-SOS complex, activate Ras-GTP, and sequentially initiate the Raf-MEK-ERK cascade reaction ^[31].

ERK enters the nucleus and promotes the expression of transcription factors such as AP-1, Elk-1, and c-Fos, regulating the transcription of cell cycle proteins (e.g., Cyclin D1) and driving the cell cycle from G1 to S phase ^[32]. Studies show that constitutive activation of PDGFRA can lead to hyperactivation of the MAPK pathway, causing uncontrolled cell proliferation, particularly in tumors and fibrotic tissues ^[33].

3.3 JAK/STAT Pathway

The JAK/STAT signal is an important pathway through which PDGFRA regulates immune responses and cell differentiation. PDGFRA activation can promote the phosphorylation of JAK1/2, thereby activating STAT1, STAT3, and STAT5 ^[34]. Activated STAT proteins enter the nucleus and promote the transcription of anti-apoptotic genes (e.g., Bcl-2, Mcl-1) ^[35]. In glioma and leukemia, upregulation of the PDGFRA-JAK/STAT signal is closely related to tumor cell survival ^[36].

Simultaneously, this pathway regulates macrophage polarization and cytokine secretion, playing a significant role in chronic inflammation and immune diseases ^[37].

3.4 PLCγ and Ca²⁺ Signaling Pathway

PDGFRA can also activate the phospholipase Cγ (PLCγ) pathway. Phosphorylation at the Y1021 site of the receptor leads to PLCγ binding, catalyzing the decomposition of PIP2 into IP3 and DAG ^[38]. IP3 induces the release of Ca²⁺ from the endoplasmic reticulum, while DAG activates PKC, thereby regulating cell migration and contractile functions ^[39]. This pathway is particularly important in the proliferation and migration of vascular smooth muscle cells; its aberrant activation is closely associated with atherosclerosis and vascular remodeling ^[40]. Furthermore, Ca²⁺ signaling can provide feedback to regulate PDGFRA phosphorylation levels, forming a dynamic balance mechanism ^[41].

3.5 Crosstalk Between Signaling Pathways

The signaling network mediated by PDGFRA is highly complex, with cross-regulation existing between different pathways. For example, PI3K/Akt can regulate the intensity of MAPK signaling by inhibiting Raf activation [42]; ERK can provide feedback to regulate PDGFRA phosphorylation, limiting its overactivation ^[43].

Additionally, PDGFRA can interact with pathways such as TGF-β, EGFR, and VEGFR, forming a multi-level signaling network ^[44]. In the tumor microenvironment, this crosstalk exacerbates uncontrolled cell growth and drug resistance ^[45].

Therefore, understanding the dynamic interactions between PDGFRA-related pathways is crucial for precision therapy.

4. PDGFRA and Diseases

Aberrant activation of PDGFRA is closely associated with various diseases, including malignant tumors, fibrotic diseases, cardiovascular diseases, and neurological disorders. Its mechanisms primarily involve constitutive activation of cell signaling, alterations in the immune microenvironment, and remodeling of the extracellular matrix.

4.1 PDGFRA and Tumors

4.1.1 Gastrointestinal Stromal Tumor (GIST)

GIST is one of the most extensively studied tumor types regarding PDGFRA. Approximately 10-15% of GISTs harbor PDGFRA mutations, the most common being the D842V mutation in exon 18, which leads to constitutive receptor activation and resistance to imatinib ^[46]. Avapritinib, as a novel highly selective inhibitor, effectively targets the D842V mutation, significantly improving patient progression-free survival ^[48].

4.1.2 Glioma and Brain Tumors

PDGFRA is frequently amplified or overexpressed in gliomas, particularly in pediatric high-grade gliomas (HGG) ^[50]. PDGFRA signaling promotes unlimited proliferation of neural glial precursor cells via the PI3K/Akt and STAT3 pathways ^[51].

In animal models, constitutive activation of PDGFRA can independently drive tumor formation, and combined with p53 loss, it significantly enhances malignancy ^[52].

4.1.3 Lung Cancer and Other Solid Tumors

PDGFRA is also aberrantly expressed in various solid tumors such as lung adenocarcinoma, colorectal cancer, and breast cancer ^[55]. Its upregulated signaling is associated with the activation of tumor stromal cells, angiogenesis, and metastasis ^[56]. For example, in non-small cell lung cancer, PDGF-AA secreted by cancer-associated fibroblasts (CAFs) can activate PDGFRA to promote tumor progression ^[57]. Inhibiting PDGFRA can reduce tumor cell invasiveness and enhance the response to immunotherapy ^[58].

4.2 Fibrosis-Related Diseases

PDGFRA signaling is aberrantly activated in fibrosis of multiple organs. It promotes fibroblast proliferation and extracellular matrix deposition, serving as a key driver of fibrogenesis. In liver fibrosis, PDGFRA promotes hepatic stellate cell activation and collagen synthesis via the Akt/mTOR pathway ^[59]. Inhibiting PDGFRA can significantly alleviate the degree of liver fibrosis ^[60]. In pulmonary fibrosis models, upregulation of PDGFRA leads to sustained activation of fibroblasts; multi-target TKIs like nintedanib improve disease progression by inhibiting PDGFRA/FGFR/VEGFR signaling ^[61].

Furthermore, in glomerulosclerosis and myocardial fibrosis, PDGFRA signaling promotes myofibroblast differentiation and enhances ECM deposition, leading to irreversible tissue remodeling ^[62].

4.3 Cardiovascular System Diseases

PDGFRA plays a dual role in vascular development and injury repair. Moderate activation promotes vascular smooth muscle proliferation and regeneration, whereas sustained overactivation leads to vascular remodeling and atherosclerosis ^[47]. Studies show that PDGFRA signaling regulates smooth muscle cell migration via the PLCγ/Ca²⁺ and ERK pathways ^[49]; its overactivation after arterial injury leads to neointima formation ^[53]. Inhibiting PDGFRA can reduce abnormal vascular smooth muscle proliferation and improve the risk of restenosis ^[8]. Therefore, PDGFRA is considered an important potential target for vascular disease intervention.

4.4 Neurological Diseases

PDGFRA is also crucial for nervous system development and repair. It is expressed in oligodendrocyte precursor cells (OPCs) and is essential for myelination and regeneration ^[9]. In neural injury or degenerative diseases, PDGFRA signaling regulates the proliferation of glial cells and axonal regeneration ^[10]. However, overactivated PDGFRA may lead to abnormal glial cell hyperplasia, associated with the formation of neuroglioma ^[54]. Therefore, maintaining the balance of PDGFRA signaling is crucial for neural homeostasis.

5. Research Progress in PDGFRA-Targeted Drugs

Currently, drug development targeting PDGFRA exhibits a trend of diversification, covering various types such as small molecule chemicals, monoclonal antibodies, and CAR-T cell therapies. As shown in the table below, in addition to multi-target drugs like ripretinib and avapritinib, which are widely approved for the treatment of gastrointestinal stromal tumors, numerous candidate drugs are in different stages of development, with their indications expanding to include pulmonary arterial hypertension, idiopathic pulmonary fibrosis, soft tissue sarcoma, and other diseases, demonstrating the broad clinical development prospects of this target.

Medications	Target (Gene Name)	Type of medication	Under investigation indications (disease names)	Institution under Research	Highest Research Stage
Ripretinib	PDGFRα x c-Kit	Small molecule pharmaceutical	Gastrointestinal stromal tumor	Deciphera Pharmaceuticals, Inc. \| Specialised Therapeutics Australia Pty Ltd. \| Specialised Therapeutics Asia Pte Ltd. \| Zai Lab (Shanghai) Co., Ltd.	Approved for Market
Apatinib	PDGFRα x c-Kit	Small molecule pharmaceuticals	Gastrointestinal stromal tumor ;\| ;Mastocytosis with myeloid features ;\| ;Systemic mastocytosis with aggressive features ;\|	Blueprint Medicines (Netherlands) BV \| Blueprint Medicines Corp. \| KeShi Pharmaceutical \| KeShi Pharmaceutical (Suzhou) Co., Ltd.	Approved for Market
Olaratumab	PDGFRα	Monoclonal antibody	X-linked ichthyosis \| Soft tissue sarcoma \| Metastatic soft tissue sarcoma \| Sarcoma	Telix Pharmaceuticals Ltd. \| Eli Lilly & Co. \| Eli Lilly Canada, Inc.	Approved for Market
Lenvatinib mesylate	FGFR1 x FGFR2 x FGFR3 x FGFR4 x PDGFRα x RET x VEGFR1 x VEGFR2 x VEGFR3 x c-Kit	Small molecule drugs	Advanced endometrial cancer ;\| ;Recurrent endometrial cancer ;\| ;Thymoma ;\| ;Advanced renal cell carcinoma, etc.	Eisai, Inc. \| Merck Sharp & Dohme Corp. \| Merck Sharp & Dohme LLC \| AiViva BioPharma, Inc. \| Eisai GmbH \| Eisai Co., Ltd. \| Eisai Europe Ltd. \| Beijing Tong Ren Tang (Boryung) Co., Ltd. \| MSD Korea Co., Ltd. \| Jiangsu Shengxian Pharmaceutical Co., Ltd.	Approved for Market
Regorafenib	BRAF V600E x CRAF x CSF-1R x DDR2 x EphA2 x FGFR1 x FRK x MAPK11 x PDGFRα x PDGFRβ x RET x Tie-2 x TrkA x VEGFR1 x VEGFR2 x VEGFR3 x c-Kit	Small molecule pharmaceuticals	Liver Cancer \| \| Hepatocellular Carcinoma \| \| Colorectal Cancer \| \| Gastrointestinal Stromal Tumor \| \| Metastatic Colorectal Cancer, etc.	Merck KGaA \| Bayer AG \| Bayer HealthCare Pharmaceuticals, Inc. \| Bayer Pharma AG \| Bristol Myers Squibb Co. \| Gustave Roussy, Cancer Campus, Grand Paris \| Sun Yat-sen University \| Amgen, Inc. \| Bayer Yakuhin Ltd. \| Bayer HealthCare AG	Approved for Market
Pazopanib	FGFR1 x FGFR3 x Flt3L x ITK x LCK x PDGFRα x PDGFRβ x VEGFR1 x VEGFR2 x VEGFR3 x c-Kit	Small molecule drug	Metastatic renal cell carcinoma ;\| ;Soft tissue tumors ;\| ;Sarcomas ;\| ;Renal cell carcinoma ;\| ;Soft tissue sarcomas, etc.	Novartis AG \| Novartis Pharmaceuticals Corp. \| Novartis Pharmaceuticals Australia Pty Ltd. \| Novartis Europharm Ltd. \| GSK Plc \| Novartis Pharma KK \| Novartis Pharma Schweiz AG	Approved for Market
Seralutinib	CSF-1R x PDGFRα x PDGFRβ x c-Kit	Small molecule pharmaceuticals	Interstitial Lung Disease-Induced Pulmonary Hypertension \| Familial Pulmonary Hypertension \| Idiopathic Pulmonary Hypertension	Gossamer Bio, Inc. \| CHIESI Farmaceutici SpA	Phase 3 Clinical
Mesylate Masitinib	LYN x PDGFRα x PDGFRβ x c-Kit	Small molecule pharmaceuticals	Amyotrophic Lateral Sclerosis ;\| ;Melanoma ;\| ;Metastatic Colorectal Cancer ;etc.	AB Science SA	Clinical Phase 3
Anti-CMV monoclonal antibody (Humabs BioMed SA)	PDGFRα	Monoclonal antibody	Cytomegalovirus Infection	IRB Barcelona \| Humabs BioMed SA	Clinical Phase 2
DCC-3009	PDGFRα x c-Kit	Small molecule drug	Gastrointestinal stromal tumor	Deciphera Pharmaceuticals, Inc.	Phase 1/2 Clinical
Ansornitib	DDR1 x DDR2 x PDGFRα x PDGFRβ	Small molecule pharmaceuticals	Idiopathic pulmonary fibrosis	Angion Biomedica Corp.	Clinical Phase 1
ICP-033	DDR1 x DDR2 x PDGFRα x PDGFRβ x VEGFR2 x VEGFR3	Small molecule drug	Locally advanced malignant solid tumor	Beijing Nuochengjianhua Pharmaceutical Technology Co., Ltd.	Clinical Phase 1
89Zr-TLX300-CDx	PDGFRα	Therapeutic Radiopharmaceuticals	Soft Tissue Sarcoma	Telix Pharmaceuticals Ltd.	Clinical Phase 1
IkT-001Pro	ABL x PDGFRα x PDGFRβ x c-Kit	Small Molecule Drug	Chronic Phase Chronic Myeloid Leukemia \| Philadelphia Chromosome Positive Chronic Granulocytic Leukemia	Inhibikase Therapeutics, Inc.	Clinical Phase 1
Ubavitinib	PDGFRα x c-Kit	Small molecule pharmaceutical	Late-stage cancer \| Advanced malignant solid tumor \| Gastrointestinal stromal tumor \| Inoperable melanoma	Ningbo Xinyuan Technology Development Co., Ltd. \| Ningbo Xinyuan Pharmaceutical Technology Co., Ltd.	Clinical Phase 1
Covalent KIT and PDGFRA Inhibitors (TU Dortmund University)	PDGFRα x c-Kit	Small molecule pharmaceuticals	Gastrointestinal stromal tumor	University of Dortmund	Preclinical
PDGFRA Targeted CAR-T (MD Anderson)	PDGFRα	CAR-T	Glioma	University of Texas MD Anderson Cancer Center	Preclinical
PDGFR-α inhibitor 6o (China Pharmaceutical University)	PDGFRα	Small molecule drug	Colorectal cancer	China Pharmaceutical University	Preclinical
KIT/PDGFRA inhibitor (Tagrisso Biopharmaceuticals)	PDGFRα x c-Kit	Chemical drug	Acute myeloid leukemia \| Gastrointestinal stromal tumor \| Mastocytosis	Shenzhen Tagiri Biopharmaceutical Co., Ltd.	Preclinical
68Ga-NOTA-CTX004	PDGFRα	Antibody-Linked Radiopharmaceutical \| Diagnostic Radiopharmaceutical	Pancreatic Ductal Adenocarcinoma	Cortalix BV	Preclinical
Compound 22 (Shanghai Institute of Materia Medica)	CSF-1R x PDGFRα x SRC family	Small molecule drug	Idiopathic pulmonary fibrosis	Shanghai Institute of Materia Medica, Chinese Academy of Sciences	Preclinical
LQFM-064	PDGFRα x c-Kit x p53	Small molecule drug	Breast cancer	Federal University of Goiás	Preclinical
Compound 4p (Sardar Patel University)	PDGFRα	Small molecule drug	Tumor	Sardar Patel University	Preclinical
6-Hydroxygenistein	PDGFRα x c-Kit	Small molecule pharmaceuticals	Gastrointestinal stromal tumor	Mohammed V University	Preclinical

(Data as of November 10, 2025, sourced from Synapse)

6. PDGFRA Research Tools

PDGFRA, as an important receptor tyrosine kinase, plays a central role in various physiological and pathological processes. Its aberrant activation is closely associated with tumors, fibrosis, cardiovascular, and neurological diseases. Cusabio provides PDGFRA recombinant protein, antibodies, and ELISA kits to support your related mechanism research and targeted drug development.

● PDGFRA Recombinant Protein

Recombinant Human Platelet-derived growth factor receptor alpha (PDGFRA), partial (Active); CSB-MP017712HU1

● PDGFRA Antibody

PDGFRA (tovetumab) Recombinant Monoclonal Antibody; CSB-RA017712MA1HU

● PDGFRA ELISA Kit

Mouse Platelet-Derived Growth Factor Soluble Receptor α,PDGFsR-α ELISA kit; CSB-E04699m

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