Researchers identify sunitinib as a senolytic targeting PDGFRβ in preclinical models

Preclinical findings demonstrate that the kinase inhibitor sunitinib selectively clears senescent human dermal fibroblasts and reduces senescent cell burden in a mouse model of lung fibrosis via PDGFRβ modulation.

Researchers from DGIST and collaborating South Korean institutions reported that sunitinib, an approved multi-targeted receptor tyrosine kinase (RTK) inhibitor, selectively induces apoptosis in senescent human dermal fibroblasts (sHDFs).

Sunitinib-induced senolysis was shown to occur via the activation of caspases-9, -3, and -7 following the suppression of PDGFRβ activation.

In a mouse model of bleomycin-induced lung fibrosis, administration of sunitinib reduced senescent cell accumulation and suppressed the expression of the senescent-associated secretory phenotype (SASP).

Genetic knockdown of PDGFRβ similarly sensitized senescent cells to death with minimal effect on non-senescent fibroblasts, confirming the target's role in senescent cell survival.

Historically, senolytic drug development has heavily concentrated on Bcl-2/Bcl-xL inhibitors and other distinct anti-apoptotic pathways.

This study establishes the RTK family, specifically PDGFRβ and its downstream JAK2-STAT3 signaling pathway, as a viable alternative mechanism for inducing senolysis.

The identification of JAK1 phosphorylation as a resistance mechanism in non-senescent cells helps explain the selectivity of sunitinib, providing key biological insights for refining future senolytic safety profiles.

The discovery that an established, clinically characterized oncology agent (sunitinib) possesses senolytic properties may accelerate target-validation timelines for companies focusing on senescence.

Demonstrated efficacy in a pulmonary fibrosis model highlights the potential for developing target-specific PDGFRβ inhibitors for localized or systemic fibrotic diseases.

Further preclinical studies to determine whether more selective PDGFRβ inhibitors can replicate the senolytic efficacy of sunitinib while minimizing the systemic toxicities associated with broad-spectrum RTK inhibition.