夜读札记（四）
一、替代药物抑制Dxd的药物代谢酶8201后端的Dxd，是“OATP1B1, OATP1B3, MATE2 - K, P -gp, MRP1和BCRP的底物”。抑制OATP1B1, OATP1B3, MATE2 - K, P -gp, MRP1和BCRP，Dxd实际能进入到癌细胞里的量就会大，疗效就会好。
1、柚皮素 Naringenin，抑制p-gp、bcrp，也抑制p450；柚皮素抑制各种炎症因子，对于防治8201的肺炎副作用也有疗效。不过柚皮素也有一定的抑制her2的作用；her2低表达的患者用可能会削弱8201前端赫赛汀的导向作用。
2、二吲哚甲烷 diindolylmethane，也是一种从西蓝花里提取出来的物质，淘宝有这种保健品卖；diindolylmethane是mrp1的抑制剂。
《Dietary bioactive diindolylmethane enhances the therapeutic efficacy of centchroman in breast cancer cells by regulating ABCB1/P-gp efflux transporter》
“ Intriguingly, DIM enhanced the intracellular concentration of CC by inhibiting the P-gp and MRP1 expression as well as activity. ”
3、环孢菌素，一种免疫抑制剂，“环孢菌素是CYP3A4的抑制剂和底物，也是CYP2C9、多种OATP(如OATP1B1、OATP1B3)和BCRP的抑制剂。”
4、昂丹司琼 Ondansetron，止吐药，是MATE2 - K的抑制剂
《Ondansetron Can Enhance Cisplatin-Induced Nephrotoxicity via Inhibition of Multiple Toxin and Extrusion Proteins (MATEs)》
以前我们还讲过，昂丹司琼是axl的抑制剂，抑制axl，可以延缓her2药的耐药。不过二甲双胍也是MATE2 - K的底物，同时在用二甲双胍的患者要注意这点
二、CDK4/6抑制剂的耐药
cdk4/6包括cdk4、cdk6。cdk4/6是关乎细胞周期的，细胞周期是所有癌细胞都有的问题，是通用靶点，并不只是乳腺癌内分泌患者才会有这两个靶点（只不过是内分泌型患者表达这两个靶点的比例比较高，乳腺癌内分泌患者基数比较大而已），更不需要一定要搭配内分泌药才能用。之前我们发过相关的论文，实际上即便是乳腺癌内分泌型，通过对病灶的免疫组化检测，也发现相当比例的病灶并不表达cdk4/6。
影响cdk4/6抑制剂耐药的主要的路径有以下这些：
1、RB1（也包括RB2和RBL1）的loss
RB1的loss 可以用极光激酶a抑制剂，可以用parp抑制剂。
2、ccne1的过表达
ccne1的过表达可以用wee1抑制剂 azd1775
3、mdm2、mdm4的过表达
mdm2、mdm4的过表达可以用apg-115
4、KRAS, HRAS, NRAS的激活
5、pi3k/akt/mtor通路的激活，主要是akt1、akt3的激活
6、FGFR1/2、fgf3的激活
fgfr1、fgfr2、fgf3的激活可以用厄达替尼等药物
7、p53突变
8、stat3的磷酸化
9、乳腺癌里 cdk6的表达太高
10、fat1的缺失
11、hippo通路中的LATS1, LAT2, and YAP发生突变
12、AURKA也就是极光激酶a的过表达
三、Fedratinib 菲达替尼对kras突变有治疗作用
《Bioinformatics Data Mining Repurposes the JAK2 (Janus Kinase 2) Inhibitor Fedratinib for Treating Pancreatic Ductal Adenocarcinoma by Reversing the KRAS (Kirsten Rat Sarcoma 2 Viral Oncogene Homolog)-Driven Gene Signature》
“KRAS (Kirsten rat sarcoma 2 viral oncogene homolog) is the major driver mutation gene for PDAC tumorigenesis. In this study, we mined cancer genomics data and identified a common KRAS-driven gene signature in PDAC, which is related to cell-cell and cell-extracellular matrix (ECM) interactions. Higher expression of this gene signature was associated with poorer overall survival of PDAC patients. Connectivity Map (CMap) analysis and drug sensitivity profiling predicted that a clinically approved JAK2 (Janus kinase 2)-selective inhibitor, fedratinib (also known as TG-101348), could reverse the KRAS-driven gene signature and exhibit KRAS-dependent anticancer activity in PDAC cells. As an approved treatment for myelofibrosis, the pharmacological and toxicological profiles of fedratinib have been well characterized. It may be repurposed for treating KRAS-driven PDAC in the future.”
Fedratinib 菲达替尼，jak2靶点的治疗骨髓纤维化的一个药，对kras突变有治疗作用。
四、NSC59984 （cas号803647-40-7）是一种广谱的p53降解剂
NSC59984 （cas号803647-40-7）是一种广谱的p53降解剂，原料药也买得到。
我目前查到的测试过的点位包括：
1、R248W（《Targeting mutant p53-R248W reactivates WT p53 function and alters the onco-metabolic profile》）
2、R175H（《NAMPT Inhibitor and P73 Activator Represses P53 R175H Mutated HNSCC Cell Proliferation in a Synergistic Manner》）
3、R273H（《Cadherin-6 type 2, K-cadherin (CDH6) is regulated by mutant p53 in the fallopian tube but is not expressed in the ovarian surface》）
4、S241F （《Small-Molecule NSC59984 Restores p53 Pathway Signaling and Antitumor Effects against Colorectal Cancer via p73 Activation and Degradation of Mutant p53》）
NSC59984有双重功效，既是突变p53的降解剂，也是p73的激活剂
p73属于p53家族，野生型p73的功效也是抑癌。
《Small-Molecule NSC59984 Restores p53 Pathway Signaling and Antitumor Effects against Colorectal Cancer via p73 Activation and Degradation of Mutant p53》 这篇论文也讲到了 降解突变p53给化疗药增敏增效的问题。
top1抑制剂伊立替康、top2抑制剂依托泊苷、顺铂这些化疗药，会激活提高p73的表达；但是突变的p53，会跟p73形成复合物，阻挠p73发挥抑癌作用。（《Chemosensitivity linked to p73 function》）
所以要降解突变的p53，解放p73，让其发挥抑癌作用。
五、BTK抑制剂Acalabrutinib和 zanubrutinib也抑制her2
1、《Acalabrutinib as a novel hope for the treatment of breast and lung cancer: an in-silico proof of concept》
“Results of the study led to the identification of ACL as a ligand that showed a high docking score and binding energy with HER-2, mTOR, and VEGFR-1 successively. Whereas, the MD simulations study has also shown good docked complex stability of ACL with HER2 and VEGFR1.”
2、《Anticancer effect of zanubrutinib in HER2-positive breast cancer cell lines》
“ We found that zanubrutinib is a potential inhibitor of the HER2 signalling pathway, displaying an antiproliferative effect in HER2-positive BCa cell lines. Zanubrutinib effectively inhibits the phosphorylation of proteins in the ERBB signalling cascade, including the downstream kinases Akt and ERK, which mediate key signals ensuring the survival and proliferation of cancer cells. We thus propose zanubrutinib as another suitable candidate for repurposing in HER2-amplified solid tumours.”
六、辛伐他汀逆转西妥昔对kras突变的耐药
《Effect of simvastatin plus cetuximab/irinotecan for KRAS mutant colorectal cancer and predictive value of the RAS signature for treatment response to cetuximab》
“Patients and methods: In this phase II study, patients received 500 mg/m(2) cetuximab, 150-180 mg/m(2) (day 1), and 80 mg simvastatin (once daily, days 1-14, every 2 weeks). The primary endpoint was the objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), the disease control rate (DCR), and safety. We also analyzed the relationship between the RAS gene expression signature score and treatment response to simvastatin/cetuximab/irinotecan.
Results: Fifty-two KRAS mutant CRC patients were enrolled. The ORR (complete response , 0; partial response , 1) was 1.9 % (95 % confidence interval , -1.8-5.6). The DCR (CR, 0; PR, 1; stable disease, 33) was 65.4 % (95 % CI, 52.5-78.3). The median PFS and OS from the time of study drug administration were 7·6 months (95 % CI, 4.4-10.8) and 12.8 months (95 % CI, 9.5-16.2), respectively. The most common grade 3/4 adverse events were anemia (28.8 %), neutropenia (13.5 %), and diarrhea (7.7 %). The RAS signature score was significantly correlated with the maximal change in target lesions from baseline (r = 0.57, P = 0.014).
Conclusion: The simvastatin/cetuximab/irinotecan regimen showed promising efficacy and safety in KRAS mutant CRC patients who failed irinotecan and oxaliplatin-based chemotherapy. ”
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