夜读札记（二）

一、对所有ALK-tki 耐药的I1171N + F1174I or I1171N + L1198H突变，对恩曲替尼耐药的NTRK1 G667C突变，ROS1融合阳性，都可以用Gilteritinib 治疗

《Gilteritinib overcomes lorlatinib resistance in ALK-rearranged cancer》

“ALK gene rearrangement was observed in 3%-5% of non-small cell lung cancer patients, and multiple ALK-tyrosine kinase inhibitors (TKIs) have been sequentially used. Multiple ALK-TKI resistance mutations have been identified from the patients, and several compound mutations, such as I1171N + F1174I or I1171N + L1198H are resistant to all the approved ALK-TKIs. In this study, we found that gilteritinib has an inhibitory effect on ALK-TKI-resistant single mutants and I1171N compound mutants in vitro and in vivo. Surprisingly, EML4-ALK I1171N + F1174I compound mutant-expressing tumors were not completely shrunk but regrew within a short period of time after alectinib or lorlatinib treatment. However, the relapsed tumor was markedly shrunk after switching to the gilteritinib in vivo model. In addition, gilteritinib was effective against NTRK-rearranged cancers including entrectinib-resistant NTRK1 G667C-mutant and ROS1 fusion-positive cancer”


二、如果血液lcn2 指标特别高，乳腺癌和黑色素瘤发生脑转移的概率特别大

《Reciprocal interactions between innate immune cells and astrocytes facilitate neuroinflammation and brain metastasis via lipocalin-2》

“Brain metastasis still encompass very grim prognosis and therefore understanding the underlying mechanisms is an urgent need toward developing better therapeutic strategies. We uncover the intricate interactions between recruited innate immune cells and resident astrocytes in the brain metastatic niche that facilitate metastasis of melanoma and breast cancer. We show that granulocyte-derived lipocalin-2 (LCN2) induces inflammatory activation of astrocytes, leading to myeloid cell recruitment to the brain. LCN2 is central to inducing neuroinflammation as its genetic targeting or bone-marrow transplantation from LCN2-/- mice was sufficient to attenuate neuroinflammation and inhibit brain metastasis. Moreover, high LCN2 levels in patient blood and brain metastases in multiple cancer types were strongly associated with disease progression and poor survival. Our findings uncover a previously unknown mechanism, establishing a central role for the reciprocal interactions between granulocytes and astrocytes in promoting brain metastasis and implicate LCN2 as a prognostic marker and potential therapeutic target.”


三、hENT1 蛋白表达的高低，是用吉西他滨敏感与否的一个生物标志物

人类平衡核苷转运蛋白(hENTs)是跨膜蛋白，促进核苷和核苷类似物(如吉西他滨)摄入细胞。如果hENT1 蛋白表达低，吉西他滨能进入癌细胞的量就小，疗效就不好。

“在接受吉西他滨治疗的患者中，hENT1低表达组的患者的中位总生存期为17.1月（95% CI=14.3~23.8），而高表达组的患者的中位总体生存期则为26.2月（95% CI=21.2~31.4）（χ21=9.87；P=0.002）。”

“In a clinical evaluation, the median progression-free survival was 24 and 11 weeks among patients with strong and weak intratumoral hENT1 immunohistochemical staining (P = 0.05), and the median overall survival was 52 and 26 weeks (P = 0.15), respectively. In conclusion, this study showed that increased hENT1 expression is associated with a stronger toxic effect of gemcitabine on BTC cell lines. ”

“Results: We found a significant association between high hENT1 expression levels and favourable outcome in terms of PFS and OS compared to cases with low hENT1 expression in leiomyosarcoma treated with gemcitabine (PFS: 6.8 vs 3.2 months, P=0.004; OS: 14.9 vs 8.5 months, P=0.007). In addition, hENT1 overexpression correlated with a significant improvement in PFS (9.3 vs 4.5 months; P=0.02) and OS (20.6 vs 10.8 months; P=0.001) in angiosarcoma patients treated with gemcitabine.”


四、植物提取物 pentagalloylglucose 抑制 UBE2T 延缓吉西他滨耐药

《Targeting UBE2T potentiates gemcitabine efficacy in pancreatic cancer by regulating pyrimidine metabolism and replication stress. Gastroenterolog》

“ Spontaneous PC mice with Ube2t deletion had a marked survival advantage after gemcitabine treatment, and UBE2T levels were positively correlated with gemcitabine resistance in clinical patients. Mechanistically, UBE2T catalyzes ring finger protein 1 (RING1)-mediated ubiquitination of p53 and relieves the transcriptional repression of ribonucleotide reductase subunits M1 and M2, resulting in unrestrained pyrimidine biosynthesis and alleviation of replication stress. Additionally, high-throughput compound library screening using organoids identified pentagalloylglucose (PGG) as a potent UBE2T inhibitor and gemcitabine sensitizer. The combination of gemcitabine and PGG diminished tumor growth in PDX models and prolonged long-term survival in spontaneous PC mice”


五、EGCG抑制fasn从而抑制fazd10，从而延缓乐伐替尼的耐药

《M6A-mediated upregulation of FZD10 regulates liver cancer stem cells properties and lenvatinib resistance through WNT/β-catenin and Hippo signaling pathways》

“Elevated FZD10 expression promotes expansion of liver CSCs and lenvatinib resistance, indicating that FZD10 expression is a novel prognostic biomarker and therapeutic target for human HCC.”

《Targeting fatty acid synthase sensitizes human nasopharyngeal carcinoma cells to radiation via
downregulating frizzled class receptor 10》

“ Results: FASN knockdown or inhibition significantly enhanced radiosensitivity of NPC cells, both in vitro and in vivo. There was a positive association between FASN and FZD10 expression in NPC cell lines grown as monolayers or xenografts, as well as human tissues. FASN knockdown reduced FZD10 expression, and rescue of FZD10 expression abolished FASN knockdown-induced enhancement of radiosensitivity. FASN and FZD10 were both negatively associated with overall survival of NPC patients. Conclusions: FASN contributes to radioresistance, possibly via FZD10 in NPC cells. Both FZD10 and FASN expressions were associated with poor outcomes of NPC patients. EGCG may sensitize radioresistance by inhibiting FASN and may possibly be developed as a radiosensitizer for better treatment of NPCs.”


六、her2-tki耐药的一些问题

《Comparative analysis of drug response and gene profiling of HER2-targeted tyrosine kinase inhibitors》 这篇论文比较好，它的主要内容是用 来那替尼、图卡替尼、拉帕替尼这三个her2靶点的TKI小分子抑制剂，去测试115种有her2扩增或者突变的各癌种的癌细胞，看药物疗效。

这篇论文的结论主要有以下几点

1、“Neratinib displayed the greatest anti-proliferative activity against HER2-mutant and EGFR-mutant models compared to the other HER2-targeted TKIs and was the most potent of the three TKIs in breast cancer models. ”
对有her2突变（非扩增）同时有egfr突变的模型和乳腺癌有her2靶点的模型，三个药里，来那替尼最敏感。

2、“Tucatinib showed excellent selectivity for HER2-amplified cell lines; however, it had minimal effect on HER2-mutant cell lines.”
图卡替尼主要是对her2扩增敏感，对her2突变效果不大。

3、“VTCN1, CDK12, and RAC1 represent three novel markers of HER2-targeted TKI sensitivity.
VTCN1 encodes the protein B7-H4 and has been previously associated with immunotherapy response in breast cancer, particularly in HER2+ breast cancer.4DK12 has been shown to induce trastuzumab resistance and stimulate HER2 signalling.Likewise, RAC1 has been implicated in resistance to chemotherapy, adiotherapy, and targeted therapies, such as trastuzumab.5his may suggest that HER2-targeted TKIs, alone or in combination with CDK12 or RAC1 inhibition, could be a more appropriate therapeutic strategy than trastuzumab for high CDK12- or RAC1-expressing HER2+ breast cancer.”
VTCN1, CDK12, and RAC1的高表达，是这三个药耐药的主要原因之一。

4、“CDK6 expression was significantly correlated with both lapatinib and tucatinib resistance. ”
CDK6的高表达与拉帕替尼、图卡替尼的耐药显著相关。

5、“High expression of several DNA damage repair genes, including ATM, BRCA1, and BRCA2, was associated with TKI insensitivity. In addition, inactivating BRCA2 mutations correlated with response to both neratinib and tucatinib ”
像atm、brca1/2 这些dna损伤修复基因的高表达，会造成her2-tki药物的不敏感。所以如果HRD评分高阳性的患者，就要考虑单用 her2-tki的疗效问题。抑制brca2会增强来那替尼和图卡替尼的疗效。

七、胸苷磷酸化酶与卡培他滨

《胸苷磷酸化酶在肿瘤细胞中的表达及与卡培他滨治疗效果的关系》

“目的探讨胸苷磷酸化酶(thymidine phosphorylase,TP)在肿瘤细胞中的表达及与卡培他滨治疗效果的关系。方法选取280例肿瘤患者,其中胃癌94例、结直肠癌101例、乳腺癌85例。检测不同类型癌症的癌组织与其对应癌旁正常组织的TP表达,对不同癌症患者均给予卡培他滨治疗,比较各组治疗效果,并观察TP表达与卡培他滨治疗效果的关系。结果胃癌、结直肠癌、乳腺癌中TP表达阳性率分别为64.89%、69.31%、81.18%,均明显高于癌旁正常组织(均P<0.01);乳腺癌TP表达阳性率明显高于胃癌与结直肠癌(均P<0.01);胃癌、结直肠癌、乳腺癌采用卡培他滨治疗后疗效比较差异有统计学意义(P<0.05),其中乳腺癌的疾病控制率明显高于胃癌(P<0.05);采用卡培他滨治疗后TP阳性患者疾病控制率明显高于TP阴性患者(90.59%比37.18%,P<0.01)。结论与正常组织比较,TP在癌组织中呈过度表达;TP阳性表达的癌症患者采用卡培他滨治疗效果更为确切,故对于TP表达阳性的患者可选择使用卡培他滨进行治疗。”