Small molecule treatments for EGFR inhibitor resistant lung cancer

用简单的术语描述研究，以便向普通观众宣传。非小细胞肺癌是一种常见的恶性肿瘤，其发病率高，发病率低，是一种常见的恶性肿瘤。非小细胞肺癌是一种常见的恶性肿瘤。在大约30%的情况下，它是由一种称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，称为激酶结构域，负责传递这些信号。为了打开信号，两个EGFR分子聚集在一起，激酶结构域促进化学反应，将一个分子中的磷酸基团添加到另一个分子中。这种化学修饰开启了癌症驱动信号。由激活的EGFR驱动的癌症可以通过称为EGFR抑制剂的药物进行治疗，这些药物与激酶结构域结合，通过阻断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希替尼（Tagrisso），它能够有效地治疗患者很长一段时间（约1-2年）。然而，不可避免的是，癌症对药物产生耐药性，疾病进展。在许多情况下，耐药性是通过EGFR蛋白的进一步变化而发展的，这意味着药物不再能有效结合。我们的项目将开发新的药物治疗方法，可以有效治疗对EGFR抑制剂（如奥希替尼）产生耐药性的癌症。这种新的治疗方法最终将在EGFR抑制剂治疗之后使用，因此，结合使用，有望显著延长非小细胞肺癌患者的生命。我们已经开发了一套能够阻止癌细胞生长的分子，这些癌细胞具有常见的EGFR变化，使其对EGFR抑制剂（包括奥希替尼）具有耐药性。目前的拨款将使我们能够利用我们有前途的线索，并将其改进到可以阻止肺癌模型中耐药肿瘤生长的程度，并为进一步改进以产生可以进展到临床试验的分子铺平道路。

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.