2023年4月时点治疗cdk12扩增的可及方案
乳腺癌里her2与cdk12高频共扩增，cdk12高倍扩增是her2抑制剂耐药的一个主要原因之一。（见《CDK12 drives breast tumor initiation and trastuzumab resistance via WNT and IRS1-ErbB-PI3K signaling》、《Comparative analysis of drug response and gene profiling of HER2-targeted tyrosine kinase inhibitors》）。自救群里多位her2、cdk12共扩增的病友常规her2治疗均不理想，其中一位做过minipdx检测，发现her2抑制剂单药抑癌率均在10%以下，曲妥珠帕妥珠双her2抑制剂方案抑制率只有24%，令人印象极其深刻。
CDK12目前没有专门的靶向药上市；用CDK1/2/5/9抑制剂dinaciclib能有效抑制CDK12（见《CDK12 Inhibition Reverses De Novo and Acquired PARP Inhibitor Resistance in BRCA Wild-Type and Mutated Models of Triple-Negative Breast Cancer》）；但dinaciclib也未上市，可及性差。
现就CDK12扩增的治疗，搜集整理出三个可及性强的方案：
一、替代药物盐酸丙卡特罗直接抑制CDK12
1、《CDK12 and PAK2 as novel therapeutic targets for human gastric cancer》：“We further identified FDA approved clinical drug procaterol can serve as an effective CDK12 inhibitor, leading to dramatic restriction of cancer cell proliferation and tumor growth in human gastric cancer cells and PDXs. ”
2、自救群友小娜与这篇论文的作者进行了联系与沟通，得知盐酸丙卡特罗以说明书常规剂量治疗cdk12扩增小规模临床试验已经开展并且取得了不错的疗效。
二、同时围堵WNT/β-catenin通路与pi3k通路
1、cdk12扩增造成her2抑制剂耐药的主要作用机制是激活 WNT/β-catenin通路与PI3K/AKT通路。
《CDK12 drives breast tumor initiation and trastuzumab resistance via WNT and IRS1-ErbB-PI3K signaling》 ：“Mechanistically, the catalytic activity of CDK12 is required for the expression of genes involved in the activation of ErbB-PI3K-AKT or WNT-signaling cascades. ”
《CDK12 inhibition enhances sensitivity of HER2+ breast cancers to HER2-tyrosine kinase inhibitor via suppressing PI3K/AKT》：“Exploring mechanisms, we found that inhibition of CDK12 attenuated PI3K/AKT signal, which usually serves as an oncogenic driver and is reactivated when HER2-positive breast cancers develop resistance to lapatinib.”
2、WNT/β-catenin通路目前没有专门的靶向药上市，有阿昔替尼、硝唑尼特、氯硝柳胺、塞来昔布等替代药物；PI3K/AKT通路有阿培利司、依维莫司、西罗莫司、白蛋白型西罗莫司等上市靶向药。
三、cdk12扩增用抗叶酸类化疗药获益可能性大
《CDK12 promotes tumorigenesis but induces vulnerability to therapies inhibiting folate one-carbon metabolism in breast cancer》 ：“Consistently, in retrospective patient cohort studies and in patient-derived xenografts, CDK12-overexpressing breast tumors show positive response to methotrexate-based chemotherapy targeting CDK12-induced metabolic alterations, while being intrinsically refractory to other types of chemotherapy. In a retrospective analysis of hormone receptor-negative and lymph node-positive breast cancer patients randomized in an adjuvant phase III trial to 1-year low-dose metronomic methotrexate-based chemotherapy or no maintenance chemotherapy, a high CDK12 status predicts a dramatic reduction in distant metastasis rate in the chemotherapy-treated vs. not-treated arm. Thus, by coupling tumor progression with metabolic reprogramming, CDK12 creates an actionable vulnerability for breast cancer therapy and might represent a suitable companion biomarker for targeted antimetabolite therapies in human breast cancers.”
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