New research published in Science Translational Medicine identifies an interplay between tumour-intrinsic and tumour-extrinsic factors that drive resistance to treatment in pancreatic ductal adenocarcinoma (PDAC). The findings provide the rationale for combined therapies that target both oncogenic signalling and the tumour microenvironment to overcome PDAC drug resistance.

Inhibitors of the RAS–MAPK pathway hold great promise as a therapeutic strategy for PDAC. However, patients rapidly develop drug resistance, explained in part by upregulation of members of the receptor tyrosine kinase family. The researchers found that the combination of RAS–MAPK inhibitors with inhibitors of focal adhesion kinase (FAK) — a non-receptor tyrosine kinase — reduced tumour growth and increased survival in several mouse models of PDAC to a greater extent than either therapy alone. Single-cell RNA sequencing and cell culture experiments revealed that cancer-associated fibroblasts in the tumour microenvironment are activated by FAK and impair the downregulation of MYC by RAS–MAPK inhibition in PDAC cells, resulting in drug resistance. “This identifies cancer-associated fibroblasts as a novel therapeutic target for overcoming RAS pathway resistance,” explains author Gregory Beatty.

发表在《科学转化医学》上的新研究确定了导致胰腺导管腺癌 （PDAC） 治疗耐药性的肿瘤内在因素和肿瘤外在因素之间的相互作用。这些发现为针对致癌信号和肿瘤微环境的联合疗法提供了基本原理，以克服 PDAC 耐药性。

RAS-MAPK 通路的抑制剂作为 PDAC 的治疗策略具有很大的前景。然而，患者迅速产生耐药性，部分原因是受体酪氨酸激酶家族成员的上调。研究人员发现，RAS-MAPK 抑制剂与粘着斑激酶 （FAK）（一种非受体酪氨酸激酶）抑制剂的组合比单独使用任何一种疗法相比，在几种 PDAC 小鼠模型中减少了肿瘤生长并提高了存活率。单细胞 RNA 测序和细胞培养实验显示，肿瘤微环境中的癌症相关成纤维细胞被 FAK 激活，并通过 PDAC 细胞中 RAS-MAPK 抑制损害 MYC 的下调，从而导致耐药性。“这将癌症相关成纤维细胞确定为克服 RAS 通路耐药性的新型治疗靶点，”作者 Gregory Beatty 解释说。