What question did this study set out to answer?

The study aims to explore the synthetic lethality of simultaneous targeting of PDPK1 and BRAFV600E in anaplastic thyroid cancer.

April 5, 2026

Abstract 5708: Dual targeting of PDPK1 and mutated BRAFV600E is synthetically lethal

Key Points

The study aims to explore the synthetic lethality of simultaneous targeting of PDPK1 and BRAFV600E in anaplastic thyroid cancer.
In vitro experiments with BRAFV600E mutant cell lines (8505C, SW1736)
Ex vivo testing using patient-derived ATC spheroids (ATC-01, ATC-02)
In vivo analysis with orthotopic xenograft models
Use of BX795 (PDPK1 inhibitor) alone and in combination with dabrafenib (BRAF inhibitor)
Assessment of tumor response through proliferation, invasion, and DNA damage markers.
BX795 alone significantly reduced cell proliferation and invasion.
Combining BX795 with dabrafenib showed strong synergistic effects, leading to a tumor volume reduction of approximately 55%.
Dual targeting inhibited compensatory activation of PI3K/AKT and MAPK pathways, preventing resistance.
Induction of DNA damage and G2/M cell-cycle arrest was observed with combined treatment, involving alterations in key cell cycle regulators.
ROS (reactive oxygen species) generation was linked to apoptosis and cell death, highlighting a ROS-CHK2-dependent mechanism.

Abstract

Abstract Anaplastic thyroid cancer (ATC) exhibits near-uniform activation of the MAPK and PI3K/AKT/mTOR pathways, driving resistance to BRAF-targeted therapies. PDPK1, a key AGC-kinase activator downstream of PI3K, integrates multiple oncogenic and stress-response pathways and represents a critical resistance node. We investigated PDPK1 inhibition using BX795 alone and with BRAF inhibition (dabrafenib) in BRAFV600E mutant in vitro (8505C, SW1736), ex vivo (patient-derived ATC spheroids ATC-01, ATC-02), and orthotopic xenograft models. BX795 monotherapy reduced cellular proliferation and invasion, and in combination with dabrafenib produced strong synergistic anticancer activity (Combination Index 1), and led to ∼55% tumor volume reduction in vivo without toxicity. Mechanistically, dual blockade of PDPK1Ser241 and MEK/ERK phosphorylation, prevented the compensatory upregulation of PI3K/AKT and MAPK pathways seen with monotherapy. The synthetic lethality of dual targeting of PDPK1 and BRAFV600E was due to induction of extensive DNA damage (γ-H2AX↑, ATM/CHK2↑), G2/M cell-cycle arrest through suppression of CDC25C, CDK1, and cyclin A2, and triggering of mitochondrial hyperpolarization with impaired oxidative phosphorylation and increased ROS generation. Elevated mitochondrial ROS amplified DNA-damage signaling, culminating in BAD dephosphorylation, caspase-3 activation, and PARP cleavage. ROS scavengers (N-acetylcysteine, MitoQ) and CHK2 inhibition partially reversed apoptosis and cell cycle arrest, confirming a ROS-CHK2-dependent cell death mechanism. Together, these findings reveal that combined PDPK1 and BRAF inhibition is synthetically lethal in BRAFV600E-mutant cancer. PDPK1 represents a targetable vulnerability for enhancing BRAFV600E-targeted cancer therapy and in other MAPK/PI3K-coactivated cancers. Citation Format: Tejinder Pal Khaket, Chandrayee Gosh, Zhongyue Yang, Electron Kebebew, . Dual targeting of PDPK1 and mutated BRAFV600E is synthetically lethal abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5708.

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Abstract 5708: Dual targeting of PDPK1 and mutated BRAFV600E is synthetically lethal

Key Points

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