Krasi+hsp90i+hdac6i的治疗模式

可用此治疗模式的患者画像
1、有kras突变+GOF型P53突变+可采用抑制β-catenin治疗策略的突变（如apc突变、ctnnb1突变等）。
2、践行精准治疗理念。（即先做大panel或全外显子基因检测、肿瘤相关蛋白全景检测、minipdx检测、肿瘤类器官药敏测试等精准检测，然后根据检测结果查找各种文献资料，再制定治疗方案的精准治疗）
3、有较强的求生欲望，风险偏好是进取型。
4、认知水平高。
5、行动能力强。（买得到原料药，会做纳米脂质体乳化剂）
6、经济上比较宽裕。

二、Krasi
Krasi用RMC-6236或 洛那法尼。
1、RMC-6236
某种程度上说RMC-6236的出现才让这个治疗模式有了现实可能性。
（1）RMC-6236单药治疗ras突变的胰腺癌
《Revolution Medicines Provides Clinical Updates from its RAS(ON) Inhibitor Portfolio》（https://ir.revmed.com/news-relea ... l-updates-its-rason）
In 76 patients with RAS mutant PDAC, RMC-6236 at 300 mg QD was generally well tolerated and showed an overall safety profile consistent with the results reported at ENA. No differentiated safety signals were observed.
The most common treatment-related adverse events (TRAEs) were rash and gastrointestinal (GI)-related toxicities that were primarily Grade 1 or 2 in severity. No Grade 3 or higher TRAEs were observed in greater than 10% of patients.
There were no treatment discontinuations due to TRAEs and the mean dose intensity was 89%.
In 37 patients with 2L RAS mutant PDAC, RMC-6236 at 300 mg QD demonstrated compelling antitumor activity.
Patients with PDAC harboring a KRAS G12X mutation (n=22) achieved a median PFS of 8.8 months (95% confidence interval (CI), 8.5 months – not estimable (NE)), while the median OS was not estimable (95% CI, NE – NE). Patients with PDAC harboring any RAS mutation (n=37) achieved a median PFS of 8.5 months (95% CI, 5.9 months – NE), while the median OS was not estimable (95% CI, 8.5 months – NE).
The proportion of patients who remained alive six months after starting treatment with RMC-6236 was 100% and 97% in patients with PDAC harboring a KRAS G12X mutation and patients with PDAC harboring any RAS mutation, respectively.
The objective response rate (ORR) was 36% and 27% in patients with PDAC harboring a KRAS G12X mutation and patients with PDAC harboring any RAS mutation, respectively.

（2）RMC-6236单药治疗ras突变的非小细胞肺癌
《Revolution Medicines Provides Clinical Updates from its RAS(ON) Inhibitor Portfolio》（https://ir.revmed.com/news-relea ... l-updates-its-rason）
In patients with previously treated NSCLC, RMC-6236 was generally well tolerated at doses of 120 mg to 220 mg QD, while the 300 mg QD dose demonstrated a higher frequency and severity of TRAEs.
In the 120 mg to 220 mg dose range, the most common TRAEs were rash and GI-related toxicities that were primarily Grade 1 or 2 in severity. No Grade 3 or higher TRAEs were observed in greater than 10% of these patients. In the 120 mg to 220 mg dose range, TRAEs leading to dose modification occurred in 41% of patients with 4% of patients discontinuing treatment due to TRAEs and the mean dose intensity was 88%.
RMC-6236 at 120 mg to 220 mg QD demonstrated encouraging antitumor activity in the population of 40 efficacy-evaluable 2L or third-line (3L) patients with NSCLC who had received immunotherapy and platinum chemotherapy but had not received docetaxel.
These patients achieved a median PFS of 9.8 months (95% CI, 6 – 12.3 months), a median OS of 17.7 months (95% CI, 13.7 months – NE) and an ORR of 38%.

（3）肿瘤是多因素驱动的，往往要同时抑制几个靶点联用几个抗癌药疗效才会好。Krasi+hsp90i+hdac6i的治疗模式中，RMC-6236的剂量可参考RMC-6236联合RMC-6291治疗kras g12c突变的肠癌的临床试验的剂量，每天一次，每次从100毫克开始吃起，根据自己的耐受和治疗情况，慢慢爬坡加量吃上去，原则上不超过300毫克。
RMC-6236的常见副作用：恶心、呕吐、腹泻、疲劳。

2、洛那法尼  Lonafarnib
洛那法尼Lonafarnib (Sch66336) 是一种有效的，具有口服活性的法尼基蛋白转移酶 (FPTase) 抑制剂，作用于 H-ras，K-ras 和 N-ras，IC50 分别为 1.9 nM，5.2 nM 和 2.8 nM
（1）CAS号：193275-84-2
（2）分子量：638.82
（3）用法用量：可以参考《Phase II study of the farnesyltransferase inhibitor lonafarnib with paclitaxel in patients with taxane-refractory/resistant nonsmall cell lung carcinoma》这篇论文讲到的洛那法尼联合紫杉醇治疗非小细胞肺癌的二期临床试验的剂量，即每天两次，每次100毫克。要注意的是，洛那法尼抗癌剂量不同于治疗儿童早衰症的剂量。
（4）常见副作用：疲劳、厌食、恶心、意识模糊、脱水、肌无力、抑郁、头痛和呼吸困难。

三、抑制hsp90对GOF型P53突变、kras突变、β-catenin的治疗作用

1、hsp90i促进GOF型突变的p53的降解
gain-of-function (GOF)功能获得型突变p53，不仅是丧失了抑癌功能，更重要的是有了促癌作用。因此对于GOF突变p53，要促进其蛋白降解，削弱其促癌功能。抑制hsp90是促进其蛋白降解的一种治疗策略。需要注意的是，p53的缺失突变不能从抑制hsp90中 获益。
《Depleting stabilized GOF mutant p53 proteins by inhibiting molecular folding chaperones: a new promise in cancer therapy》
The heat shock protein HSP90 chaperone machinery is highly activated in cancer versus normal tissues, rendering them resistant to proteotoxic stress by supporting proper folding – and preventing aggregation – of conformationally aberrant oncoproteins including mutp53.8, 9 Both classes of mutp53 (structural and DNA-contact) require HSP90 for protection from degradation by their E3 ubiquitin ligases Mdm2 and CHIP (Figure 1a). Thus, combined inhibition of Hsp90 and its obligatory regulator cytosolic HDAC6 by small molecule inhibitors 17DMAG and Vorinostat/SAHA, respectively, or by Hsp90 inhibitor ganetespib alone extends overall survival of R175H (structural class) and R248Q (DNA-contact class) mutp53 animals by 30–59% and strongly prevents T-lymphomagenesis (the main tumor type in these mice). Surprisingly, although these are pleiotropic drugs, in no instance do p53-null mice benefit from Hsp90 inhibition7 (Figure 1a). These anti-cancer effects are concomitant with mutp53 degradation and cancer cell apoptosis, indicating tumor addiction to highly stabilized mutp53. Of note, a positive feed-forward loop from mutp53 to Hsp90 may further reinforce mutp53 stabilization (Figure 1a, green arrow). Thus, in HER2/EGFR-positive breast cancer, GOF mutp53 R175H activates the master heat shock transcription factor Hsf1, which in turn upregulates the heat shock response including HSP90, which then further stabilizes mutp53, HER2 and EGFR.9 This loop likely contributes to the vulnerability of such cancers to Hsp90 inhibition.

2、kras突变反向激活上游的ERBB1-4，抑制ERBB1-4对kras突变有治疗作用；ERBB1-4都是hsp90的客户蛋白，抑制hsp90促进ERBB1-4的降解
（1）《Receptor Tyrosine Kinase Signaling Networks Define Sensitivity to ERBB Inhibition and Stratify Kras-Mutant Lung Cancers》
Furthermore, pan-ERBB inhibition reduced the clonogenicity of KL cultures, which was exacerbated by combinatorial MEK inhibition, whereas combinatorial MEK and FGFR inhibition suppressed clonogenicity of AC cultures. Importantly, in vivo studies confirmed KL-selective sensitivity to pan-ERBB inhibition, which correlated with high ERBB ligand expression and activation of ERBB receptors, implying that ERBB network activity may serve as a predictive biomarker of drug response. Interestingly, in human NSCLCs, phosphorylation of EGFR or ERBB3 was frequently detected in ASCs and squamous cell carcinomas. We conclude that analysis of in situ ERBB signaling networks in conjunction with ex vivo drug response profiling and biochemical dissection of adaptive RTK activities may serve as a valid diagnostic approach to identify tumors sensitive to ERBB network inhibition.
（2）《The ERBB network facilitates KRAS-driven lung tumorigenesis》
KRAS is the most frequently mutated driver oncogene in human adenocarcinoma of the lung. There are presently no clinically proven strategies for treatment of KRAS-driven lung cancer. Activating mutations in KRAS are thought to confer independence from upstream signaling; however, recent data suggest that this independence may not be absolute. We show that initiation and progression of KRAS-driven lung tumors require input from ERBB family receptor tyrosine kinases (RTKs): Multiple ERBB RTKs are expressed and active from the earliest stages of KRAS-driven lung tumor development, and treatment with a multi-ERBB inhibitor suppresses formation of KRASG12D-driven lung tumors. We present evidence that ERBB activity amplifies signaling through the core RAS pathway, supporting proliferation of KRAS-mutant tumor cells in culture and progression to invasive disease in vivo. Brief pharmacological inhibition of the ERBB network enhances the therapeutic benefit of MEK (mitogen-activated protein kinase kinase) inhibition in an autochthonous tumor setting. Our data suggest that lung cancer patients with KRAS-driven disease may benefit from inclusion of multi-ERBB inhibitors in rationally designed treatment strategies.
（3）《Hsp90 inhibition overcomes HGF-triggering resistance to EGFR-TKIs in EGFR-mutant lung cancer by decreasing client protein expression and angiogenesis》
Heat shock protein90 (Hsp90) is a 90 kDa molecular chaperone for proteins that include EGFR, Met, and echinoderm microtubule-associated proetin-like-4-the anaplastic lymphoma kinase.
（4）《Targeted delivery of heat shock protein 90 inhibitors prevents growth of HER2-positive tumor》
This is because HER2 is an HSP90 client protein, making it very sensitive to HSP90 inhibition。
（5）《HSP90 inhibition blocks ERBB3 and RET phosphorylation in myxoid/round cell liposarcoma and causes massive cell death in vitro and in vivo》
EGFR and ERBB3 are clients of HSP90 that help complex formation and RTK activation. Treatment of cultured MLS cells with HSP90 inhibitor 17-DMAG, caused loss of RET and ERBB3 phosphorylation and lead to rapid cell death.

3、抑制hsp90促进β-catenin的降解
《Direct targeting of HSP90 with daurisoline destabilizesβ-catenin to suppress lung cancer tumorigenesis》
Furthermore, our data from Drug Affinity Responsive Target Stability (DARTS), isothermal titration calorimetry (ITC) and a series of functional assays demonstrated that daurisoline could target HSP90 directly and disrupt its interaction with β-catenin, therefore increasing the ubiquitin-mediated proteasomal degradation of β-catenin. This study reveals that daurisoline could be a promising therapeutic strategy for the treatment of lung cancer.

4、hsp90抑制剂目前已有Pimitespib上市
Pimitespib (TAS-116)是一种新型的HSP90小分子抑制剂，HSP90α和HSP90β的Ki值分别为34.7 nmol/L和21.3 nmol/L。TAS-11并不抑制其他ATP酶，如HSP70(IC50 >200 μmol/L)。
（1）CAS号：1260533-36-5
（2）分子量：454.53
（3）用法用量：说明书单药剂量是每天160毫克，每周连续吃五天停两天；周而复始。
Krasi+hsp90i+hdac6i的治疗模式中联药使用，可以考虑从每天80-100毫克吃起，慢慢爬坡加量吃，根据自己的耐受和治疗情况来定。
（4）常见副作用：腹泻、恶心、夜盲症、血肌酐增加、味觉障碍、食欲下降、眼部异常


四、抑制hdac6对GOF型P53突变、kras突变、β-catenin的治疗作用
1、抑制hdac6是 促进GOF型突变P53蛋白降解的另一个治疗策略
《SAHA shows preferential cytotoxicity in mutant p53 cancer cells by destabilizing mutant p53 through inhibition of the HDAC6-Hsp90 chaperone axis》
Mutant p53 (mutp53) cancers are surprisingly dependent on their hyperstable mutp53 protein for survival, identifying mutp53 as a potentially significant clinical target. However, exploration of effective small molecule therapies targeting mutp53 has barely begun. Mutp53 hyperstabilization, a hallmark of p53 mutation, is cancer cell-specific and due to massive upregulation of the HSP90 chaperone machinery during malignant transformation. We recently showed that stable complex formation between HSP90 and its mutp53 client inhibits E3 ligases MDM2 and CHIP, causing mutp53 stabilization. Histone deacetylase (HDAC) inhibitors (HDACi) are a new class of promising anti-cancer drugs, hyperacetylating histone and non-histone targets. Currently, suberoylanilide hydroxamic acid (SAHA) is the only FDA-approved HDACi. We show that SAHA exhibits preferential cytotoxicity for mutant, rather than wild-type and null p53 human cancer cells. Loss/gain-of-function experiments revealed that although able to exert multiple cellular effects, SAHA's cytotoxicity is caused to a significant degree by its ability to strongly destabilize mutp53 at the level of protein degradation. The underlying mechanism is SAHA's inhibition of HDAC6, an essential positive regulator of HSP90. This releases mutp53 and enables its MDM2- and CHIP-mediated degradation. SAHA also strongly chemosensitizes mutp53 cancer cells for chemotherapy due to its ability to degrade mutp53. This identifies a novel action of SAHA with the prospect of SAHA becoming a centerpiece in mutp53-specific anticancer strategies.

2、HDAC调节突变型KRAS的乙酰化状态和致癌活性，抑制hdac6对kras突变肿瘤有治疗作用
《HDAC6 and SIRT2 regulate the acetylation state and oncogenic activity of mutant K-RAS》
Activating point mutations in K-RAS are extremely common in cancers of the lung, colon, and pancreas and are highly predictive of poor therapeutic response. One potential strategy for overcoming the deleterious effects of mutant K-RAS is to alter its posttranslational modification. Although therapies targeting farnesylation have been explored, and have ultimately failed, the therapeutic potential of targeting other modifications remains to be seen. Recently, it was shown that acetylation of lysine 104 attenuates K-RAS transforming activity by interfering with GEF-induced nucleotide exchange. Here, the deacetylases HDAC6 and SIRT2 were shown to regulate the acetylation state of K-RAS in cancer cells. By extension, inhibition of either of these enzymes has a dramatic impact on the growth properties of cancer cells expressing activation mutants of K-RAS. These results suggest that therapeutic targeting of HDAC6 and/or SIRT2 may represent a new way to treat cancers expressing mutant forms of K-RAS.

3、EGF诱导的β-catenin核定位受HDAC6依赖性脱乙酰化作用的调节；抑制hdac6对β-catenin高表达的肿瘤有治疗作用
《HDAC6 is required for epidermal growth factor-induced beta-catenin nuclear localization》
Nuclear translocation of beta-catenin is a hallmark of Wnt signaling and is associated with various cancers. In addition to the canonical Wnt pathway activated by Wnt ligands, growth factors such as epidermal growth factor (EGF) also induce beta-catenin dissociation from the adherens junction complex, translocation into the nucleus, and activation of target genes such as c-myc. Here we report that EGF-induced beta-catenin nuclear localization and activation of c-myc are dependent on the deacetylase HDAC6. We show that EGF induces HDAC6 translocation to the caveolae membrane and association with beta-catenin. HDAC6 deacetylates beta-catenin at lysine 49, a site frequently mutated in anaplastic thyroid cancer, and inhibits beta-catenin phosphorylation at serine 45. HDAC6 inactivation blocks EGF-induced beta-catenin nuclear localization and decreases c-Myc expression, leading to inhibition of tumor cell proliferation. These results suggest that EGF-induced nuclear localization of beta-catenin is regulated by HDAC6-dependent deacetylation and provide a new mechanism by which HDAC inhibitors prevent tumor growth.

4、目前没有专门的hdac6抑制剂上市，一般都是用泛hdac抑制剂Vorinostat伏立诺他。伏立诺他对hdac6的ic50值在10nm左右。
Krasi+hsp90i+hdac6i的治疗模式中联药用伏立诺他，可以考虑每天一次，与食物一起服用，每次从100毫克开始吃起 ，慢慢爬坡加量吃上去，不超过每天300毫克；每周连续吃五天 ，停2天。
伏立诺他的常见副作用是胃肠道症状（如腹泻、恶心、厌食、体重下降、呕吐、便秘）、疲劳、发冷、血小板减少、贫血（可能需要调整剂量或停药）、味觉障碍、口干；PE、DVT、高血糖。

MC-6236或洛那法尼+ Pimitespib +伏立诺他，某种程度上说 ，胰腺癌、肠癌，才算真正有了对症的靶向药治疗方案。