Shi Rocky, Farnsworth Dylan A, Febres-Aldana Christopher A, Chow Justine L M, Sheena Ravinder, Atwal Tejveer, Gomez Marti Juan Luis, Li Samantha, Thomas Kiersten N, Lee Che-Min, Awrey Shannon J, McDonald Paul C, Somwar Romel, Dedhar Shoukat, Ladanyi Marc, Bennewith Kevin L, Lockwood William W
Department of Integrative Oncology, BC Cancer Research Institute, Vancouver, BC, Canada.
Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Oncogene. 2025 May 31. doi: 10.1038/s41388-025-03461-6.
Combating resistance to targeted therapy remains a major challenge to improving lung cancer care. Epithelial-mesenchymal transition (EMT) in tumour cells is an established non-genetic resistance mechanism to EGFR tyrosine kinase inhibitors (TKI) that is also associated with worse outcome in patients. Here we demonstrate that integrin-linked kinase (ILK) is an important driver of EMT-mediated TKI resistance in lung adenocarcinoma (LUAD) by promoting a drug-tolerant persister (DTP) cell phenotype. Our results indicate that high ILK expression is associated with EMT in LUAD patients and that genetic suppression of ILK can limit EMT progression and reduce the viability of DTP cells by impairing YAP activation, ultimately improving osimertinib (Osi) sensitivity in LUAD cells. Importantly, LUAD cells with high ILK expression are able to persist during EGFR-TKI treatment, acquiring additional genetic and phenotypic alterations to develop EGFR-TKI resistance. To improve clinical translatability of our findings, we showed that pharmacological inhibition of ILK can suppress EMT and improve Osi response in LUAD cells. Lastly, we found that strong immunohistochemistry staining of ILK in patient biopsies was significantly associated with and may be used to predict receptor tyrosine kinase-independent mechanisms of EGFR-TKI resistance. Overall, our results suggest that ILK is an important regulator of EGFR-TKI response and may be exploited as a predictor for acquired resistance, providing evidence for co-targeting ILK with EGFR to better control minimal residual disease and EGFR-TKI resistance in lung cancer.
对抗靶向治疗耐药性仍然是改善肺癌治疗的一项重大挑战。肿瘤细胞中的上皮-间质转化（EMT）是一种已确定的对EGFR酪氨酸激酶抑制剂（TKI）的非遗传耐药机制，也与患者的较差预后相关。在此，我们证明整合素连接激酶（ILK）通过促进耐药性持久细胞（DTP）表型，是肺腺癌（LUAD）中EMT介导的TKI耐药的重要驱动因素。我们的结果表明，高ILK表达与LUAD患者的EMT相关，并且ILK的基因抑制可通过损害YAP激活来限制EMT进展并降低DTP细胞的活力，最终提高LUAD细胞对奥希替尼（Osi）的敏感性。重要的是，具有高ILK表达的LUAD细胞在EGFR-TKI治疗期间能够持续存在，获得额外的基因和表型改变以产生EGFR-TKI耐药性。为了提高我们研究结果的临床可转化性，我们表明对ILK的药理学抑制可抑制LUAD细胞中的EMT并改善Osi反应。最后，我们发现患者活检中ILK的强免疫组织化学染色与EGFR-TKI耐药的受体酪氨酸激酶非依赖性机制显著相关，并且可用于预测该机制。总体而言，我们的结果表明ILK是EGFR-TKI反应的重要调节因子，可作为获得性耐药的预测指标，为将ILK与EGFR共同靶向以更好地控制肺癌中的微小残留病和EGFR-TKI耐药性提供了证据。
