Targeting the DNA replication stress phenotype of KRAS mutant cancer cells.
Targeting the DNA replication stress phenotype of KRAS mutant cancer cells.
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DOI：
10.1038/s41598-021-83142-y
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发表时间：
2021-02-11
影响因子：
4.6
通讯作者：
Willers H
中科院分区：
文献类型：
--
作者：
Al Zubaidi T;Gehrisch OHF;Genois MM;Liu Q;Lu S;Kung J;Xie Y;Schuemann J;Lu HM;Hata AN;Zou L;Borgmann K;Willers H
突变型KRAS是一种常见的肿瘤驱动因子，通常会对抗癌治疗（如放射治疗）产生抗性。这些肿瘤中的DNA复制应激可能构成治疗责任，但知之甚少。在这里，使用单分子DNA纤维分析，我们首先在一组未受干扰的等基因和非等基因癌细胞系中表征了基线复制应激。与观察到的增强的复制应激相关，我们发现与野生型细胞相比，KRAS突变体中胞质双链DNA的水平增加。然而，尽管有这种表型，复制应激诱导剂未能选择性地影响受CHK1保护的KRAS突变细胞。类似地，与野生型细胞相比，所研究的大多数外源性应激物并没有差异地增加KRAS突变体中的胞质DNA积累。然而，我们发现质子辐射能够减缓分叉进程，并优先诱导KRAS突变细胞中的分叉停滞。质子处理也部分逆转了与突变KRAS相关的辐射抗性。在KRAS突变存在下质子的细胞效应与影响复制的其他药物形成鲜明对比，突出了质子引起的潜在DNA损伤的独特性质。总之，我们的研究结果提供了与突变的KRAS相关的复制应激反应的见解，这可能最终产生新的治疗机会。
Mutant KRAS is a common tumor driver and frequently confers resistance to anti-cancer treatments such as radiation. DNA replication stress in these tumors may constitute a therapeutic liability but is poorly understood. Here, using single-molecule DNA fiber analysis, we first characterized baseline replication stress in a panel of unperturbed isogenic and non-isogenic cancer cell lines. Correlating with the observed enhanced replication stress we found increased levels of cytosolic double-stranded DNA in KRAS mutant compared to wild-type cells. Yet, despite this phenotype replication stress-inducing agents failed to selectively impact KRAS mutant cells, which were protected by CHK1. Similarly, most exogenous stressors studied did not differentially augment cytosolic DNA accumulation in KRAS mutant compared to wild-type cells. However, we found that proton radiation was able to slow fork progression and preferentially induce fork stalling in KRAS mutant cells. Proton treatment also partly reversed the radioresistance associated with mutant KRAS. The cellular effects of protons in the presence of KRAS mutation clearly contrasted that of other drugs affecting replication, highlighting the unique nature of the underlying DNA damage caused by protons. Taken together, our findings provide insight into the replication stress response associated with mutated KRAS, which may ultimately yield novel therapeutic opportunities.
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影响因子：
11.2
作者：
Gilad O;Nabet BY;Ragland RL;Schoppy DW;Smith KD;Durham AC;Brown EJ
通讯作者：
Brown EJ
染色体不稳定性通过胞质DNA反应驱动转移。
影响因子：
64.8
作者：
Bakhoum SF;Ngo B;Laughney AM;Cavallo JA;Murphy CJ;Ly P;Shah P;Sriram RK;Watkins TBK;Taunk NK;Duran M;Pauli C;Shaw C;Chadalavada K;Rajasekhar VK;Genovese G;Venkatesan S;Birkbak NJ;McGranahan N;Lundquist M;LaPlant Q;Healey JH;Elemento O;Chung CH;Lee NY;Imielenski M;Nanjangud G;Pe'er D;Cleveland DW;Powell SN;Lammerding J;Swanton C;Cantley LC
通讯作者：
Cantley LC
影响因子：
45.3
作者：
Eberhard, DA;Johnson, BE;Hillan, KJ
通讯作者：
Hillan, KJ
影响因子：
3.7
作者：
Kleiman, Laura B.;Krebs, Angela M.;Haigis, Kevin M.
通讯作者：
Haigis, Kevin M.
影响因子：
3.7
作者：
Chow OS;Kuk D;Keskin M;Smith JJ;Camacho N;Pelossof R;Chen CT;Chen Z;Avila K;Weiser MR;Berger MF;Patil S;Bergsland E;Garcia-Aguilar J
通讯作者：
Garcia-Aguilar J