Small molecule treatments for EGFR inhibitor resistant lung cancer

EGFR 抑制剂耐药性肺癌的小分子治疗

• 批准号: MR/X004872/1
• 负责人: Michael Waring
• 金额: $ 137.05万
• 依托单位: Newcastle University
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FX004872%2F1
• 关键词: Small; molecule; treatments; EGFR; inhibitor

Describe the research in simple terms in a way that could be publicised to a general audience. If awarded, this will be made publicly available and applicants are responsible for ensuring that the content is suitable for publication.Non-small cell lung cancer is one of the most common forms of cancer. In about 30% of cases, it is driven by changes in a protein called epidermal growth factor receptor (EGFR). These mutations cause an increase in the signals that instruct the cancer cells to divide, invade tissues and spread through the body. EGFR is a receptor that spans the cell wall. Part of the protein on the inside of the cell, called the kinase domain, is responsible for transmitting these signals. To switch the signal on, two molecules of EGFR come together and the kinase domain promotes a chemical reaction that adds groups called a phosphates from one molecule to the other. This chemical modification switches on the cancer driving signals.Cancers that are driven by activated EGFR can be treated by drugs, called EGFR inhibitors, that bind to the kinase domain and stop the chemical reaction by blocking the binding of the molecules that provide the phosphate groups that are transferred. Perhaps the most successful drug currently is osimertinib (Tagrisso), which is able to effectively treat patients for a substantial period (about 1-2 years). However, inevitably the cancers become resistant the drug and disease progresses. In many cases, the resistance develops through further changes to the EGFR protein that mean that the drug can no longer effectively bind.Our project will develop new drug treatments that can effectively treat cancers that have become resistant to EGFR inhibitors like osimertinib. The new treatment will ultimately be used subsequently to EGFR inhibitor therapy and thus, in conjunction, will be expected to significantly extend the lives of non-small cell lung cancer patients.We have developed a set of molecules that are able to prevent the growth of cancer cells that have the common EGFR changes that make them resistant to EGFR inhibitors, including osimertinib. This current grant will allow us to take our promising leads and improve them to a point that they can be shown to stop resistant tumours growing in models of lung cancer and pave the way to further improvements to produce a molecule that can be progressed into clinical trials.

以一种可以向一般受众宣传的方式，用简单的术语描述这项研究。如果获奖，它将被公之于众，申请者有责任确保内容适合发表。非小细胞肺癌是最常见的癌症之一。在大约30%的病例中，它是由一种名为表皮生长因子受体(EGFR)的蛋白质的变化驱动的。这些突变导致指示癌细胞分裂、侵入组织并在体内扩散的信号增加。EGFR是一种跨越细胞壁的受体。细胞内部的一部分蛋白质，称为激活域，负责传递这些信号。为了打开信号，EGFR的两个分子聚集在一起，激活域促进化学反应，将一个分子中称为磷酸盐的基团添加到另一个分子中。这种化学修饰启动了癌症驱动信号。由激活的EGFR驱动的癌症可以通过药物治疗，称为EGFR抑制剂，这种药物与激活域结合，并通过阻止提供转移的磷酸基团的分子的结合来停止化学反应。也许目前最成功的药物是奥西美替尼(Tagrisso)，它能够有效地治疗患者很长一段时间(大约1-2年)。然而，不可避免的是，癌症会对药物产生抗药性，疾病会继续发展。在许多情况下，耐药性是通过EGFR蛋白的进一步变化而形成的，这意味着药物不能再有效地结合。我们的项目将开发新的药物治疗方法，可以有效地治疗对EGFR抑制剂如奥西美替尼产生抗药性的癌症。这种新的治疗方法最终将在EGFR抑制剂治疗之后使用，因此，联合使用将有望显著延长非小细胞肺癌患者的生命。我们开发了一套能够防止癌细胞生长的分子，这些癌细胞具有共同的EGFR变化，使它们对包括奥西美替尼在内的EGFR抑制剂具有耐药性。这笔目前的拨款将使我们能够取得有希望的领先成果，并将其改进到可以阻止耐药肿瘤在肺癌模型中生长的程度，并为进一步改进生产一种可以进入临床试验的分子铺平道路。

项目成果

Targeting Cytotoxic Agents through EGFR-Mediated Covalent Binding and Release.

• DOI: 10.1021/acs.jmedchem.3c00845
• 发表时间: 2023-09-14
• 期刊: JOURNAL OF MEDICINAL CHEMISTRY
• 影响因子: 7.3
• 作者: Morese, Pasquale A.;Anthony, Nahoum;Bodnarchuk, Michael;Jennings, Claire;Martin, Mathew P.;Noble, Richard A.;Phillips, Nicole;Thomas, Huw D.;Wang, Lan Z.;Lister, Andrew;Noble, Martin E. M.;Ward, Richard A.;Wedge, Stephen R.;Stewart, Hannah L.;Waring, Michael J.
• 通讯作者: Waring, Michael J.