黑色素皮膚瘤具有強大的 DNA 修復和活性氧(ROS)清除能力，導致這種癌症 有很強的先天輻射抗性，限制了放射性治療的療效。因此，針對支持其輻射抗性 機制背後的代謝運作，成為了一個有前景的治療策略。在本研究中，我們探討了 選擇性麩醯胺酸酶抑制劑 Telaglenastat (CB-839) 在黑色素瘤中的放射增敏潛力。 我們發現抗輻射細胞株(A2058 及 C32)有較高的 GAC/GS(Glutaminase C to Glutamine Synthetase)比值，這種獨特的代謝表現型可以作為有潛力的治療預測生 物標記。利用 CB-839 干擾代謝的依賴性，能有效弱化黑色素皮膚瘤清除 ROS 及 DNA 損傷修復的能力，借此達到令人鼓舞的放射增敏效果。值得注意的是，其 增敏效果背後的細胞死亡機制因不同細胞株而有所差異。C32 因無法修復的 DNA 斷裂而走向典型細胞凋亡 (Canonical apoptosis);而 A2058 則死於由致命生物能 量危機所引發的衰老相關代謝崩潰 (Senescence-associatedmetaboliccollapse)。總 結而言，我們的研究結果證實 CB-839 作為一種廣效型放射增敏劑，能夠克服機 制的異質性。除此之外，我們發現 GAC/GS 比值作為患者分類的指標，有效支 持整合代謝標靶策略以提升放射治療的療效。;Malignant melanoma exhibits intrinsic radioresistance driven by robust DNA repair and reactive oxygen species (ROS) scavenging capabilities， limiting radiotherapy efficacy. Consequently， targeting the metabolic engines supporting these defenses offers a promising therapeutic strategy. Here， we investigated the radiosensitizing potential of telaglenastat (CB-839)， a selective glutaminase inhibitor， in melanoma. We identified that radioresistant cell lines (A2058 and C32) display a distinct metabolic phenotype characterized by a high Glutaminase C to Glutamine Synthetase (GAC/GS) ratio， which serves as a robust predictive biomarker. Targeting this dependency with CB-839 effectively dismantled antioxidant defenses and DNA repair capacity， resulting in significant radiosensitization. Notably， the lethal outcomes were different between these two cell lines: C32 cells underwent canonical apoptosis driven by unresolvable DNA breaks， whereas A2058 cells succumbed to a senescence-associated metabolic collapse precipitated by a fatal bioenergetic crisis. Collectively， our findings demonstrate that CB-839 acts as a broad-spectrum radiosensitizer capable of overcoming mechanistic heterogeneity. We propose the GAC/GS ratio as a tool for patient stratification， supporting the integration of metabolic targeting to enhance radiotherapeutic outcomes.
