延缓阿培利司等pik3ca靶向药的耐药

一、阿培利司等pik3ca靶向药的主要耐药机制包括不限于：
1、胰岛素反馈
) b7 y+ `; ?  a, z8 y8 Y( U2、IGF-1R 激活
3、PTEN loss
4、AKT 、 mTOR 的重新激活
5、myc的过表达
0 b1 M( i2 ^1 X- E  c. L3 H* ^# j6、MAPK/MEK通路的激活
/ W  V  e) Q3 @* p: d4 u4 I. I5 O7、RSKs的过表达
& V9 Z3 X$ {5 B  X8、JAK2/STAT5通路的激活
9、IL-6-STAT3的反馈
' t2 E) U' p# d' q$ {8 i10、PIM1的过表达
# S! K6 W$ Q- A5 j, v3 @11、Collagene 2/Integrin-b1/SRC 表达升高
$ K* i% O3 c5 @) C+ \$ K4 c12、AXL过表达
13、JNK激活
14、TCF7、β-catenin、GSK3β 激活
15、NF1 loss
16、PI3Kβ 激活
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! g& u7 a) Q/ z二、一些延缓阿培利司等pik3ca靶向药耐药的具体措施

1、吡格列酮治疗高胰岛素血症和高血糖，抑制GSK3β，延缓阿培利司的耐药。
（1）《Treating Alpelisib-Induced Hyperinsulinemia in Patients with Advanced Breast Cancer - A Real-Life Experience》
PIK3CA activating mutations are found in 40% of advanced breast cancer and are associated with worse prognosis. PI3K blockage is associated with insulin resistance, leading to hyperglycemia and hyperinsulinemia. Alpelisib is the first PI3K inhibitor used in cancer treatment. Laboratory evidence indicated that alpelisib-induced hyperinsulinemia offsets the drug's efficacy, but insulin levels were not tested in the clinical trials that evaluated alpelisib for breast cancer. Hyperglycemia could also interfere with anti-tumor effects of PI3K inhibitors by inducing Immune tolerance and altered mitochondrial metabolism. We have monitored insulin levels in 4 breast cancer patients with concomitant metabolic syndrome treated with alpelisib, and pre-treated patients with baseline increased insulin levels with pioglitazone, a potent insulin sensitizer, to target both hyperinsulinemia and hyperglycemia, and we report the treatment course of these patients. All patients achieved glycemic control and were able to maintain alpelisib dose intensity. Duration of response to alpelisib was longer than anticipated in this treatment setting. Insulin dynamics confirmed the efficacy of pioglitazone as a specific on-target hypoglycemic and hypo-insulinemic agent in the unique setting of PI3K blockade. Our experience suggests that targeting hyperinsulinemia in patients with is safe and feasible and results in good metabolic and oncologic outcomes.
（2）《Artificial intelligence framework identifies candidate targets for drug repurposing in Alzheimer's disease》
In vitro experiments showed that pioglitazone downregulated glycogen synthase kinase 3 beta (GSK3β) and cyclin-dependent kinase (CDK5) in human microglia cells
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2、去氢骆驼蓬碱(Harmine) 抑制 PI3Kβ
3 o& p/ v$ l& q  W% ]6 M, p《去氢骆驼蓬碱对宫颈癌的抑制作用及其分子机制研究》
1) 在宫颈癌细胞中,Harmine可明显地抑制AKT、GSK3β、ERK1/2、P38等蛋白的磷酸化水平;2)在宫颈癌细胞中,Harmine可通过抑制PI3K/AKT/GSK3β信号通路来抑制细胞的增殖;3)在Harmine对PI3K/AKT/GSK3β信号通路的调控中,p110β亚基起着主导作用;干扰p110β亚基后,Harmine对Hela细胞中的AKT磷酸化水平的影响明显大于干扰p110α亚基后对AKT磷酸化水平的影响。

# @* _5 h" j: `  c& M  \: w0 C4 ?3、Vortioxetine hydrobromide 抑制 jak2、src
; Y5 {; q# A% E- u1 o: ]. X6 H《Vortioxetine hydrobromide inhibits the growth of gastric cancer cells in vivo and in vitro by targeting JAK2 and SRC》
/ L$ s+ f. Z( d0 kGastric cancer is the fourth leading cause of cancer deaths worldwide. Most patients are diagnosed in the advanced stage. Inadequate therapeutic strategies and the high recurrence rate lead to the poor 5-year survival rate. Therefore, effective chemopreventive drugs for gastric cancer are urgently needed. Repurposing clinical drugs is an effective strategy for discovering cancer chemopreventive drugs. In this study, we find that vortioxetine hydrobromide, an FDA-approved drug, is a dual JAK2/SRC inhibitor, and has inhibitory effects on cell proliferation of gastric cancer. Computational docking analysis, pull-down assay, cellular thermal shift assay (CETSA) and in vitro kinase assays are used to illustrate vortioxetine hydrobromide directly binds to JAK2 and SRC kinases and inhibits their kinase activities. The results of non-reducing SDS-PAGE and Western blotting indicate that vortioxetine hydrobromide suppresses STAT3 dimerization and nuclear translocation activity. Furthermore, vortioxetine hydrobromide inhibits the cell proliferation dependent on JAK2 and SRC and suppresses the growth of gastric cancer PDX model in vivo. These data demonstrate that vortioxetine hydrobromide, as a novel dual JAK2/SRC inhibitor, curbs the growth of gastric cancer in vitro and in vivo by JAK2/SRC-STAT3 signaling pathways. Our results highlight that vortioxetine hydrobromide has the potential application in the chemoprevention of gastric cancer.

4、姜黄素 抑制STAT3-PIM1异二聚体
《In-silico and in-vitro investigation of STAT3-PIM1 heterodimeric complex: Its mechanism and inhibition by curcumin for cancer therapeutics》
The functional activity among STAT3 and PIM1, are key signaling events for cancer cell function. Curcumin, a diarylheptanoid isolated from turmeric, effectively inhibits STAT3 signaling. Selectively, we attempted to address interactions of STAT3, PIM1 and Curcumin for therapeutic intervention using in silico and in vitro experimental approaches. Firstly, protein-protein interactions (PPI) between STAT3-PIM1 by molecular docking studies reflected salt bridges among Arg279 (STAT3)-Glu140 (PIM1) and Arg282 (STAT3)-Asp100 (PIM1), with a binding affinity of -38.6 kcal/mol. Secondly, molecular dynamics simulations of heterodimeric STAT3-PIM1 complex with curcumin revealed binding of curcumin on PIM-1 interface of the complex through hydrogen bonds (Asp155) and hydrophobic interactions (Leu13, Phe18, Val21, etc.) with a binding energy of -7.3 kcal/mol. These PPIs were confirmed in vitro by immunoprecipitation assays in MDA-MB-231 cells. Corroborating our results, expression levels of STAT3 and PIM1 decreased after curcumin treatment. We observed that PIM1 interacts with STAT3 and these functional interactions are disrupted by curcumin. The calculated band energy gap of heterodimeric STAT3-PIM1-Curcumin complex was of 9.621 kcal/mol. The present study revealed the role of curcumin in STAT3/PIM1 signaling and its binding affinity to the complex for design of advanced cancer therapeutics.

5、氯硝柳胺抑制β-catenin、GSK3β、stat3、myc、mtor
（1）《The magic bullet: Niclosamide》
n particular, niclosamide inhibits multiple oncogenic pathways such as Wnt/β-catenin, Ras, Stat3, Notch, E2F-Myc, NF-κB, and mTOR and activates tumor suppressor signaling pathways such as p53, PP2A, and AMPK.
+ R8 X  j8 B! m（2）《Repurposing Niclosamide for Targeting Pancreatic Cancer by Inhibiting Hh/Gli Non-Canonical Axis of Gsk3β》
Niclosamide (Nic), an FDA-approved anthelmintic drug, is reported to have anti-cancer efficacy and is being assessed in clinical trials for various solid tumors. Based on its ability to target multiple signaling pathways, in the present study, we evaluated the therapeutic efficacy of Nic on pancreatic cancer (PC) in vitro. We observed an anti-cancerous effect of this drug as shown by the G0/G1 phase cell cycle arrest, inhibition of PC cell viability, colony formation, and migration. Our results revealed the involvement of mitochondrial stress and mTORC1-dependent autophagy as the predominant players of Nic-induced PC cell death. Significant reduction of Nic-induced reactive oxygen species (ROS) and cell death in the presence of a selective autophagy inhibitor spautin-1 demonstrated autophagy as a major contributor to Nic-mediated cell death. Mechanistically, Nic inhibited the interaction between BCL2 and Beclin-1 that supported the crosstalk of autophagy and apoptosis. Further, Nic treatment resulted in Gsk3β inactivation by phosphorylating its Ser-9 residue leading to upregulation of Sufu and Gli3, thereby negatively impacting hedgehog signaling and cell survival. Nic induced autophagic cell death, and p-Gsk3b mediated Sufu/Gli3 cascade was further confirmed by Gsk3β activator, LY-294002, by rescuing inactivation of Hh signaling upon Nic treatment. These results suggested the involvement of a non-canonical mechanism of Hh signaling, where p-Gsk3β acts as a negative regulator of Hh/Gli1 cascade and a positive regulator of autophagy-mediated cell death. Overall, this study established the therapeutic efficacy of Nic for PC by targeting p-Gsk3β mediated non-canonical Hh signaling and promoting mTORC1-dependent autophagy and cell death.
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/ f8 p& J% D8 l4 _$ k4 _+ {( W6、NF1 loss 可用NAC从而延缓阿培利司等pik3ca靶向药耐药
" V$ m) L) ]0 {《N-acetylcysteine overcomes NF1 loss-driven resistance to PI3Kα inhibition in breast cancer》
A genome-wide PiggyBac transposon-mediated screen and a resistance screen in a PIK3CAH1047R-mutated murine tumor model reveal NF1 loss in mammary tumors resistant to the phosphatidylinositol 3-kinase α (PI3Kα)-selective inhibitor alpelisib. Depletion of NF1 in PIK3CAH1047R breast cancer cell lines and a patient-derived organoid model shows that NF1 loss reduces sensitivity to PI3Kα inhibition and correlates with enhanced glycolysis and lower levels of reactive oxygen species (ROS). Unexpectedly, the antioxidant N-acetylcysteine (NAC) sensitizes NF1 knockout cells to PI3Kα inhibition and reverts their glycolytic phenotype. Global phospho-proteomics indicates that combination with NAC enhances the inhibitory effect of alpelisib on mTOR signaling. In public datasets of human breast cancer, we find that NF1 is frequently mutated and that such mutations are enriched in metastases, an indication for which use of PI3Kα inhibitors has been approved. Our results raise the attractive possibility of combining PI3Kα inhibition with NAC supplementation, especially in patients with drug-resistant metastases associated with NF1 loss.
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% k8 o" F( G9 L, z7、杨梅素抑制MEK、MTOR、IGF1R
! }. e3 ~6 L, P- f2 h( w（1）《Myricetin is a novel natural inhibitor of neoplastic cell transformation and MEK1》
+ R) k5 y& m2 r& y9 ~Myricetin strongly inhibited MEK1 kinase activity and suppressed TPA- or EGF-induced phosphorylation of extracellular signal-regulated kinase (ERK) or p90 ribosomal S6 kinase, downstream targets of MEK. Moreover, myricetin inhibited H-Ras-induced cell transformation more effectively than either PD098059, a MEK inhibitor, or resveratrol.
+ w# R2 ~/ G* l2 S) w（2）《Structure-based grafting and identification of kinase-inhibitors to target mTOR signaling pathway as potential therapeutics for glioblastoma》
5 V, C: `! o2 f3 W. r( D* SStructural examination revealed diverse nonbonded interactions such as hydrogen bonds, hydrophobic forces and van der Waals contacts across the complex interface of mTOR with myricetin, conferring both stability and specificity for the mTOR-inhibitor binding.
+ C$ p3 P, I1 x9 p/ ?: ]（3）《Screening and biological evaluation of myricetin as a multiple target inhibitor insulin, epidermal growth factor, and androgen receptor; in silico and in vitro》
  [( R% W2 Y" u2 J- h" k+ {Calculated docking free energy yielded the excellent dock score for the myricetin when docked with proteins EGFR, IR, and AR\ER.
8 S& ]! S, w* p7 M& {9 r- w4 O3 zTreatment with the myricetin led to down-regulation of mRNA expression of EGFR, IR, mTOR, and Bcl-2. Although, further in vitro and in vivo experimental studies are required for the experimental validation of our findings.

8、吗丁啉、昂丹司琼抑制AXL
《In silico screening of FDA approved drugs on AXL kinase and validation for breast cancer cell line》
* }' H! S4 C3 H" _, kThe Domperidone drug molecule is showing a very good in vitro inhibition value become an attracted molecule for drug repurposing for breast cancer. The best QSAR from a 37 training set molecules generated with R2 of 0.91 and Q2 of 0.86.
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9、高三尖杉酯碱注射液抑制myc、pi3k/akt/mtor、IL-6/STAT3
& h  `, p2 v: S; \9 R! A（1）《Homoharringtonine deregulates MYC transcriptional expression by directly binding NF-κB repressing factor》
& c& [% Z' e  ]5 R7 O# ^7 n8 ^3 l& YHHT significantly decreases the expression of KIT, a frequently mutated and/or highly expressed gene in t(8;21) AML, in concert with MYC down-regulation.
' u/ [  B5 R+ Y( k3 L& l) Z) `（2）《Uncovering the action mechanism of homoharringtonine against colorectal cancer by using network pharmacology and experimental evaluation》
7 H  k; `6 w; q% x) _& }HHT treatment resulted in the inactivation of PI3K/AKT/mTOR signaling in CRC cells
（3）“Homoharringtonine (HHT)是一种具有抗肿瘤特性的植物生物碱，通过与核糖体A位点的相互作用阻止蛋白质合成的初始延伸步骤，从而抑制蛋白质的翻译。Homoharringtonine可逆地抑制IL-6诱导的STAT3酪氨酸705磷酸化和减少抗凋亡蛋白的表达。”

- I+ H4 u0 n# N2 X10、褪黑素
《Synergistic actions of Alpelisib and Melatonin in breast cancer cell lines with PIK3CA gene mutation》
  X! s* ]3 }& O) T6 \( mKey findings: MTT assay revealed that MDA-MB-453 and T-47D showed reduction in cell viability in all groups, especially in the MDA-MB-453 treated with Melatonin + Alpelisib. MDA-MB-468 presents reduction in cell migration only with Melatonin, while in the lines with mutation, the treatment of Melatonin + Alpelisib caused inhibition of cell migration. PI3K, p-AKT, mTOR and HIF-1α were inhibited after treatment with Melatonin + Alpelisib in MDA-MB-453 and T-47D lines. The expression of caspase-3 increased in all groups in MDA-MB-453 and T-47D cells, being the increase more pronounced in the Melatonin + Alpelisib group.
) z5 x2 O' c" y7 t* aSignificance: These results indicate that the combined use of Melatonin and Alpelisib may be more effective in inhibiting BC in women carrying the PIK3CA gene mutation than either treatment alone.