Siegman Alexander, Shaykevich Aaron, Chae Danbee, Silverman Isaac, Goel Sanjay, Maitra Radhashree
Department of Biology, Yeshiva University, New York, NY 10033, USA.
Department of Medical Oncology, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ 08901, USA.
Curr Issues Mol Biol. 2024 Jul 16;46(7):7530-7547. doi: 10.3390/cimb46070447.
The gene is mutated in approximately 45% of colorectal cancer patients. There are currently very few targeted treatments or therapies equipped to directly inhibit due to its unusual structural intricacies. Erlotinib, an EGFR inhibitor, has previously been demonstrated to reduce cell viability by inducing autophagy in lung cancer cell lines with varying EGFR mutations. In contrast to lung cancer cells, evidence is provided herein for the first time that erlotinib treatment in colorectal cancer (CRC) cell lines reduces autophagy and still results in decreased cell viability. However, the effects of erlotinib in CRC cell lines containing a wildtype gene were different than in cells carrying a mutant gene. We show that there is significantly more downregulation of autophagy in mutant CRC cells compared to wildtype cells, both at transcriptional and translational levels, suggesting that the mutation is advantageous for cancer growth, even in the presence of erlotinib. Cell viability results determined that wildtype CRC cells had significantly more cell death compared to mutant cells. Using patient mRNA datasets, we showed that there was a significant correlation between the presence of the mutation and the expression of autophagy proteins. Additionally, through molecular dynamics simulations, we develop a blueprint for and autophagy protein interaction and the impact of the mutation on autophagy protein regulation. Overall, this is the first report of erlotinib treatment in CRC cells that assesses autophagy, and we demonstrate that autophagy activity is downregulated in these cells. This effect is not only greater in cells carrying a mutation compared to wildtype cells, but the mutant cells also have increased cell viability compared to wildtype cells. We hypothesize that the difference in cell viability and autophagy expression between mutant and wildtype cells after treatment with erlotinib can be of therapeutic value to treat CRC patients carrying mutations.
在大约45%的结直肠癌患者中，该基因发生了突变。由于其结构异常复杂，目前几乎没有能够直接抑制它的靶向治疗方法。厄洛替尼是一种表皮生长因子受体（EGFR）抑制剂，此前已被证明可通过诱导不同EGFR突变的肺癌细胞系自噬来降低细胞活力。与肺癌细胞不同，本文首次提供证据表明，在结直肠癌细胞系中，厄洛替尼治疗可降低自噬，但仍会导致细胞活力下降。然而，厄洛替尼在含有野生型该基因的结直肠癌细胞系中的作用与携带突变型该基因的细胞不同。我们发现，与野生型细胞相比，该基因突变的结直肠癌（CRC）细胞在转录和翻译水平上自噬的下调明显更多，这表明即使在存在厄洛替尼的情况下，该基因突变也有利于癌症生长。细胞活力结果显示，野生型CRC细胞的细胞死亡明显多于该基因突变的细胞。使用患者mRNA数据集，我们表明该基因突变的存在与自噬蛋白的表达之间存在显著相关性。此外，通过分子动力学模拟，我们绘制了该基因与自噬蛋白相互作用以及该基因突变对自噬蛋白调节影响的蓝图。总体而言，这是关于厄洛替尼治疗CRC细胞并评估自噬的首次报告，我们证明这些细胞中的自噬活性被下调。这种效应在携带该基因突变的细胞中不仅比野生型细胞更大，而且该基因突变的细胞与野生型细胞相比细胞活力也有所增加。我们假设，厄洛替尼治疗后该基因突变和野生型细胞在细胞活力和自噬表达上的差异对于治疗携带该基因突变的CRC患者可能具有治疗价值。
