PFKFB3 Inhibition Sensitizes DNA Crosslinking Chemotherapies by Suppressing Fanconi Anemia Repair.
PFKFB3 Inhibition Sensitizes DNA Crosslinking Chemotherapies by Suppressing Fanconi Anemia Repair.
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DOI：
10.3390/cancers13143604
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发表时间：
2021-07-18
期刊：
影响因子：
5.2
通讯作者：
Gustafsson NMS
中科院分区：
文献类型：
--
作者：
Ninou AH;Lehto J;Chioureas D;Stigsdotter H;Schelzig K;Åkerlund E;Gudoityte G;Joneborg U;Carlson J;Jonkers J;Seashore-Ludlow B;Gustafsson NMS
破坏DNA的化疗药物，如铂类药物，是癌症治疗的基石。这种治疗的效果与癌细胞的DNA修复能力密切相关，因为超过可耐受阈值的DNA损伤最终会导致细胞死亡。癌细胞通常具有不受调控的DNA修复机制，这使得它们最初对破坏DNA的化疗更加敏感。不幸的是，随着时间的推移，癌细胞往往通过重新连接它们的DNA损伤反应通路来对这种治疗产生抗药性。在这里，我们确定了以公认的抗癌靶点6-磷酸果糖-2-激酶/果糖-2，6-二磷酸酶3(PFKFB3)为靶点，小分子抑制剂KAN0438757在癌症中过度表达，选择性地使癌细胞对铂类药物敏感，包括耐药癌细胞，而不影响正常细胞。在机制上，PFKFB3通过调节Fanconi贫血(FA)DNA修复途径，促进对铂诱导的DNA链间交联(ICL)的耐受和修复。因此，靶向PFKFB3开辟了治疗的可能性，以提高ICL诱导的癌症治疗的疗效。由铂类化疗药物产生的链间交联链(ICL)的复制修复是由Fanconi贫血(FA)修复途径协调的，以确保解决停滞的复制分叉和维持基因组的完整性。在这里，我们确定了癌症相关糖酵解酶PFKFB3对FA修复的新调节，该酶对复制相关的ICL修复和癌细胞生存具有功能影响。抑制PFKFB3在阻断细胞活力和恢复耐药模型中的敏感性方面显示出与铂化合物的癌症特异性协同作用。值得注意的是，这种协同作用与DNA损伤诱导的PFKFB3在癌症转化时的染色质关联有关，这种关联在铂耐药时进一步增加。FA途径的激活以ATR和FANCM依赖的方式触发PFKFB3组装成核焦点。阻断PFKFB3活性会扰乱关键FA修复因子的组装，从而阻止分叉重新启动。这导致复制细胞的能力丧失，无法通过S期进行，复制细胞中的DNA损伤积累，以及叉状塌陷。我们进一步验证了在癌症患者的体外培养中，PFKFB3对FA修复的依赖调节。总的来说，靶向PFKFB3开辟了治疗的可能性，以提高ICL诱导的癌症治疗的有效性。
DNA-damaging chemotherapeutics, such as platinum drugs, are cornerstones in cancer treatment. The efficacy of such treatment is intimately linked to the DNA repair capacity of the cancer cells, as DNA damage above a tolerable threshold culminates in cell death. Cancer cells often have deregulated DNA repair mechanisms, making them initially more sensitive to DNA-damaging chemotherapies. Unfortunately, over time, cancer cells often develop resistance to such treatments by rewiring their DNA damage response pathways. Here, we identify that targeting the recognized anti-cancer target 6-phosphofructo-2-kinase/fructose-2,6,-bisphophatase 3 (PFKFB3), commonly overexpressed in cancer, with the small molecule inhibitor KAN0438757, selectively sensitizes cancer cells to platinum drugs, including treatment-resistant cancer cells, while sparing normal cells. Mechanistically, PFKFB3 promotes tolerance to and the repair of platinum-induced DNA interstrand crosslinks (ICLs) through modulation of the Fanconi anemia (FA) DNA repair pathway. Thus targeting PFKFB3 opens up therapeutic possibilities to improve the efficacy of ICL-inducing cancer treatments. Replicative repair of interstrand crosslinks (ICL) generated by platinum chemotherapeutics is orchestrated by the Fanconi anemia (FA) repair pathway to ensure resolution of stalled replication forks and the maintenance of genomic integrity. Here, we identify novel regulation of FA repair by the cancer-associated glycolytic enzyme PFKFB3 that has functional consequences for replication-associated ICL repair and cancer cell survival. Inhibition of PFKFB3 displays a cancer-specific synergy with platinum compounds in blocking cell viability and restores sensitivity in treatment-resistant models. Notably, the synergies are associated with DNA-damage-induced chromatin association of PFKFB3 upon cancer transformation, which further increases upon platinum resistance. FA pathway activation triggers the PFKFB3 assembly into nuclear foci in an ATR- and FANCM-dependent manner. Blocking PFKFB3 activity disrupts the assembly of key FA repair factors and consequently prevents fork restart. This results in an incapacity to replicate cells to progress through S-phase, an accumulation of DNA damage in replicating cells, and fork collapse. We further validate PFKFB3-dependent regulation of FA repair in ex vivo cultures from cancer patients. Collectively, targeting PFKFB3 opens up therapeutic possibilities to improve the efficacy of ICL-inducing cancer treatments.
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影响因子：
64.8
作者：
Ray Chaudhuri A;Callen E;Ding X;Gogola E;Duarte AA;Lee JE;Wong N;Lafarga V;Calvo JA;Panzarino NJ;John S;Day A;Crespo AV;Shen B;Starnes LM;de Ruiter JR;Daniel JA;Konstantinopoulos PA;Cortez D;Cantor SB;Fernandez-Capetillo O;Ge K;Jonkers J;Rottenberg S;Sharan SK;Nussenzweig A
通讯作者：
Nussenzweig A
影响因子：
5.2
作者：
Lehto J;Huguet Ninou A;Chioureas D;Jonkers J;Gustafsson NMS
通讯作者：
Gustafsson NMS
p53 通过抑制 PFKFB3 表达并促进戊糖磷酸途径来协调 DNA 修复和核苷酸合成。
影响因子：
4.6
作者：
Franklin DA;He Y;Leslie PL;Tikunov AP;Fenger N;Macdonald JM;Zhang Y
通讯作者：
Zhang Y
影响因子：
64.8
作者：
Bartkova, J;Horejsi, Z;Bartek, J
通讯作者：
Bartek, J
影响因子：
16
作者：
Ciccia, Alberto;Ling, Chen;West, Stephen C.
通讯作者：
West, Stephen C.