J Thorac Oncol

Chemotherapy continues to be the standard treatment for patients non-eligible to targeted or immune-based therapies; however, treatment resistance remains a major clinical challenge. We previously found that expression levels of DSTYK, a poorly explored dual serine/threonine and tyrosine kinase frequently amplified in cancer, identifies lung cancer patients exhibiting poor response to immune checkpoint inhibitors and showed that its inhibition sensitizes to immunotherapy. Seeking to explore the potential of DSTYK targeting in additional indications, we investigated the functional relevance and actionability of DSTYK in lung cancer chemoresistance. We show that DSTYK depletion specifically sensitizes lung cancer cells to taxane-based chemotherapy, particularly in combination with carboplatin. Mechanistically, DSTYK ablation remodels the cytoskeleton and impairs distant invasion and metastatic outgrowth in vivo. DSTYK downregulation sensitizes both primary and metastatic lung tumors to chemoimmunotherapy treatment leading to tumor regression in mouse models. Consistently, clinical data of early - in the neoadjuvant and adjuvant settings- and advanced lung cancer patients show a strong correlation between DSTYK amplification and taxane resistance, underscoring the clinical significance of our findings to inform treatment decision-making. Collectively, our data indicates that DSTYK amplification may be a predictor of resistance to taxane-based treatments and represents an actionable target for these patients.