This week, we profile a recent publication in Oncogene by Dr. William Lockwood‘s lab (pictured).
Since establishing his own research group at BC Cancer in 2014, Dr. Lockwood has applied integrative genomics, including analyses of human tumors, functional mouse model studies, and chemical screens, to uncover critical genes, pathways, and potential targeted therapies regarding lung cancer.
Learn more about the lab’s findings in the paper, “Drug tolerance and persistence to EGFR inhibitor treatment are mediated by an ILK-SFK-YAP signaling axis in lung adenocarcinoma,” in our Q&A with Dr. William Lockwood and Rocky Shi.
Can you provide a brief overview of your lab’s current research focus?
Our lab is focused on understanding the biological basis of lung cancer initiation, progression, and response to therapy. We integrate genomic sequencing of patient tumors with functional screens in cell lines, organoid cultures, and genetically engineered mouse models to dissect the mechanisms of tumor development and treatment resistance. Current efforts span identifying factors that increase susceptibility to lung cancer, characterizing drug-tolerant persister cell states, and defining how specific mutations and signaling pathways drive lineage plasticity, immune evasion, and metastatic progression. Ultimately, our goal is to leverage these insights to develop more effective strategies for early detection, prevention, and treatment of lung cancer.
What is the significance of the findings in this publication?
This study addresses one of the central challenges in lung cancer treatment: why tumors often relapse despite initial responses to targeted therapies. We found that integrin-linked kinase (ILK) is a critical driver of epithelial-to-mesenchymal transition (EMT) and the survival of drug-tolerant persister (DTP) cells in EGFR-mutant lung adenocarcinoma. Using in vitro models and xenograft systems, we demonstrated that ILK promotes YAP/TEAD-dependent transcriptional programs that enable persister cells to withstand EGFR inhibition. Importantly, pharmacologic or genetic suppression of ILK impaired EMT, reduced DTP survival, and sensitized tumors to targeted therapy. These findings identify ILK as a novel vulnerability in non-genetic drug resistance and provide mechanistic insight into how microenvironmental and adhesion-mediated cues shape tumor cell persistence.
What are the next steps for this research?
Building on these findings, we aim to evaluate whether ILK inhibition can be combined with EGFR inhibitors to prevent the emergence of drug-tolerant persister cells and delay or overcome resistance in vivo. We are extending our studies into patient-derived xenografts and organoid models to determine whether ILK represents a broadly targetable vulnerability across oncogene-driven lung cancers. In parallel, we are investigating the crosstalk between ILK-mediated adhesion signaling, YAP/TEAD activity, and immune evasion pathways to explore therapeutic combinations that may both eliminate persisters and enhance antitumor immunity. Ultimately, our goal is to translate these preclinical findings into rational combination strategies for clinical testing.
Did anything in your results surprise you?
One of the most surprising aspects of this work was the degree to which ILK regulated transcriptional programs associated with EMT and survival. We did not initially anticipate that ILK would exert such broad effects on lineage plasticity and therapy tolerance. This finding reshapes how we think about integrin signaling in cancer and highlights a previously underappreciated role for adhesion-linked kinases in driving adaptive resistance.
Is the application of your research a primary motivator for you? If not, would you share what is?
While potential applications are a strong motivator—particularly the possibility of improving durability of targeted therapy responses—the primary driver for our lab is uncovering the fundamental biology of lung cancer. Understanding how tumor cells adapt under therapeutic pressure not only advances the field conceptually but also generates new therapeutic ideas. Our motivation is rooted in making discoveries that bridge basic cancer biology and translational opportunities to ultimately benefit patients.
This work was supported by an operating grant from the Cancer Research Society, with additional support from the Canadian Institutes of Health Research (CIHR). Lead author Rocky Shi was supported by a CIHR Doctoral Fellowship.
