Non-small cell lung cancer (NSCLC) is often characterized by mutually exclusive mutations in the epidermal growth factor receptor (EGFR) or the guanosine triphosphatase KRAS. We hypothesized that blocking EGFR palmitoylation, previously shown to inhibit EGFR activity, might alter downstream signaling in the KRAS-mutant setting. Here, we found that blocking EGFR palmitoylation, by either knocking down the palmitoyltransferase DHHC20 or expressing a palmitoylation-resistant EGFR mutant, reduced activation of the kinase PI3K, the abundance of the transcription factor MYC, and the proliferation of cells in culture, as well as reduced tumor growth in a mouse model of KRAS-mutant lung adenocarcinoma. Knocking down DHHC20 reduced the growth of existing tumors derived from human KRAS-mutant lung cancer cells and increased the sensitivity of these cells to a PI3K inhibitor. Palmitoylated EGFR interacted with the PI3K regulatory subunit PIK3R1 (p85) and increased the recruitment of the PI3K heterodimer to the plasma membrane. Alternatively, blocking palmitoylation increased the association of EGFR with the MAPK adaptor Grb2 and decreased that with p85. This binary switching between MAPK and PI3K signaling, modulated by EGFR palmitoylation, was only observed in the presence of oncogenic KRAS. These findings suggest a mechanism whereby oncogenic KRAS saturates signaling through unpalmitoylated EGFR, reducing formation of the PI3K signaling complex. Future development of DHHC20 inhibitors to reduce EGFR-PI3K signaling could be beneficial to patients with KRAS-mutant tumors.

中文翻译：

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阻断 EGFR 棕榈酰化抑制 PI3K 信号传导和突变型 KRAS 肺肿瘤发生。

非小细胞肺癌 (NSCLC) 通常以表皮生长因子受体 (EGFR) 或鸟苷三磷酸酶 KRAS 中相互排斥的突变为特征。我们假设阻断 EGFR 棕榈酰化（先前显示可抑制 EGFR 活性）可能会改变 KRAS 突变环境中的下游信号传导。在这里，我们发现通过敲低棕榈酰转移酶 DHHC20 或表达抗棕榈酰化的 EGFR 突变体来阻断 EGFR 棕榈酰化，可以减少激酶 PI3K 的激活、转录因子 MYC 的丰度以及培养细胞的增殖。因为在 KRAS 突变型肺腺癌小鼠模型中肿瘤生长减少。敲低 DHHC20 减少了源自人类 KRAS 突变肺癌细胞的现有肿瘤的生长，并增加了这些细胞对 PI3K 抑制剂的敏感性。Palmitoylated EGFR 与 PI3K 调节亚基 PIK3R1 (p85) 相互作用并增加 PI3K 异二聚体向质膜的募集。或者，阻断棕榈酰化增加了 EGFR 与 MAPK 接头 Grb2 的关联，并降低了与 p85 的关联。这种由 EGFR 棕榈酰化调节的 MAPK 和 PI3K 信号之间的二元转换仅在存在致癌 KRAS 的情况下观察到。这些发现表明了一种机制，即致癌 KRAS 通过未棕榈酰化的 EGFR 使信号饱和，从而减少 PI3K 信号复合物的形成。