DSTYK Inhibition Sensitizes NSCLC to Taxane-Based Chemotherapy.

Introduction: Chemotherapy continues to be the standard treatment for patients noneligible for targeted or immune-based therapies; nevertheless, 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, identified patients with lung cancer exhibiting poor response to immune checkpoint inhibitors, and found 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.

Methods: In silico analysis to study the differential sensitivity to paclitaxel, carboplatin, pemetrexed, and cisplatin drugs was performed using pan-cancer human cancer cell line DSTYK CN data downloaded from Depmap portal (https://depmap.org/portal/depmap/). Two cohorts of patients with lung cancer were used. An adjuvant cohort composed of patients with advanced IV-stage lung adenocarcinoma treated with carboplatin plus paclitaxel or carboplatin plus pemetrexed in the first line from VHIO; A neoadjuvant cohort including resectable stage IIIA or IIIB NSCLC tumor samples of patients from NADIM I and NADIM II clinical trials perioperative treated with nivolumab plus chemotherapy (carboplatin + paclitaxel). DSTYK CN was assessed by fluorescence in situ hybridization and quantitative reverse transcription-polymerase chain reaction. Proteomics and bioinformatic analyses were performed to study differentially expressed protein signatures. Functional in vitro experiments (adhesion, migration, and invasion) in both murine and human systems, and in vivo lung orthotopic, intracardiac, and intratibial xenograft and syngeneic models complete the study.

Results: 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 patients with early and advanced lung cancer-in the neoadjuvant and adjuvant settings-show a strong correlation between DSTYK amplification and taxane resistance, underscoring the clinical significance of our findings to inform treatment decision-making.

Conclusions: 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.