Homo sapiens Raw sequence reads. Homo sapiens

Nasopharyngeal carcinoma (NPC) is a malignant head and neck cancer with high morbidity in Southeast Asia, however the pathogenic mechanism of this disease is poorly understood. Using integrative pharmacogenomics, we found that NPC subtypes maintained distinct molecular features, drug responsiveness, and graded radiation sensitivity. The epithelial carcinoma (EC) subtype was characterized by activations of microtubule polymerization and defective mitotic spindle checkpoint related genes, while sarcomatoid carcinoma (SC) and mixed sarcomatoid-epithelial carcinoma (MSEC) subtypes exhibited enriched epithelial-mesenchymal transition and invasion promoting genes, which was well correlated with their morphological features. Furthermore, patient-derived organoid (PDO) based drug test identified potential subtype-specific treatment regimens in that SC and MSEC subtypes were sensitive to microtubule inhibitors, whereas EC subtype was more responsive to EGFR inhibitors, which was synergistically enhanced by combining with radiotherapy. Through combinational chemoradiotherapy (CRT) screening, effective CRT regimens were also suggested for patients showing less sensitivity to radiation. Altogether, our study provided the first example of applying integrative pharmacogenomics to establish a personalized precision oncology for NPC subtype-guided therapies.