核內琥珀酰輔酶A 合成酶 β 次單元（SUCLG2）與表皮生長因子受體（EGFR）之協同作用，驅動血管內皮生長因子 A（VEGFA）依賴的進行性前列腺癌 EGFR 酪胺酸激酶抑制劑（EGFR-TKI）抗藥性

徐志豪¹、溫玉清^1,2,3

1.臺北市立萬芳醫院-委託臺北醫學大學辦理, 泌尿科;

2. 臺北醫學大學醫學院泌尿學科;

3. 臺北醫學大學泌尿腎臟研究中心

Nuclear SUCLG2–EGFR cooperativity drives VEGFA-dependent EGFR-TKI resistance in advanced prostate cancer

Chih-Hao Hsu¹, Yu-Ching Wen^1,2,3

1. Department of Urology, Wan Fang Hospital, Taipei Medical University, Taipei 11031, Taiwan;

2. Department of Urology, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan;

3. TMU Research Center of Urology and Kidney, Taipei Medical University, Taipei 11031, Taiwan.

Background:

EGFR tyrosine-kinase inhibitors (TKIs) show limited benefit in advanced prostate cancer (PCa) because ERK signaling persists despite receptor blockade. We propose that the TCA-cycle enzyme SUCLG2 acts in the nucleus with phosphorylated EGFR to amplify VEGFA transcription, sustaining EGFR–ERK output and driving TKI resistance under androgen suppression or EGF exposure.

Materials and Methods:

Castration-resistant (CRPC) and neuroendocrine PCa (NEPC) cell lines and organoids were modeled under androgen inhibition or EGF stimulation. SUCLG2 was perturbed by overexpression or CRISPR knockout. Under erlotinib, we measured ERK activity, proliferation, sphere formation, and xenograft growth. ChIP/CUT&RUN mapped SUCLG2–EGFR occupancy at AT-rich elements in the VEGFA regulatory region. Targeted metabolomics quantified succinate. VEGFA re-expression tested rescue. A signature-reversal screen nominated small-molecule SUCLG2 antagonists, evaluated alone and with erlotinib in vitro, in NEPC organoids, and in small-cell PCa xenografts. Clinical and preclinical specimens were profiled for nuclear SUCLG2/EGFR and VEGFA.

Results:

Androgen inhibition or EGF increased SUCLG2, raised succinate, and promoted nuclear SUCLG2–pEGFR complexes at VEGFA elements, boosting VEGFA and preserving EGFR–ERK signaling under erlotinib. SUCLG2 overexpression conferred TKI resistance, enhanced self-renewal/sphere formation, and accelerated xenografts; SUCLG2 deletion restored TKI sensitivity and suppressed malignant traits. VEGFA re-expression partially rescued growth and signaling in SUCLG2-deficient cells, identifying VEGFA as a key effector. Phenethyl isothiocyanate (PEITC) functionally antagonized SUCLG2, attenuated SUCLG2/VEGFA/EGFR signaling, and synergized with erlotinib to inhibit proliferation, organoid viability, and small-cell PCa xenografts without overt toxicity. Patient samples showed progressive nuclear enrichment of SUCLG2 and EGFR with elevated VEGFA in CRPC/NEPC.

Conclusion:

Nuclear SUCLG2–EGFR cooperativity sustains VEGFA-reinforced EGFR–ERK signaling and underlies EGFR-TKI resistance in advanced PCa. Pharmacologic SUCLG2 antagonism (e.g., PEITC) synergizes with EGFR-TKIs and, together with biomarkers of nuclear SUCLG2–EGFR and high VEGFA, supports a rational co-targeting strategy for CRPC/NEPC.