Small cell transformation of fusion-positive lung cancer resistant to ROS1 inhibition.

Histologic transformation from non-small cell to small cell lung cancer has been reported as a resistance mechanism to targeted therapy in -mutant and fusion-positive lung cancers. Whether small cell transformation occurs in other oncogene-driven lung cancers remains unknown. Here we analyzed the genomic landscape of two pre-mortem and 11 post-mortem metastatic tumors collected from an advanced, fusion-positive lung cancer patient, who had received sequential ROS1 inhibitors. Evidence of small cell transformation was observed in all metastatic sites at autopsy, with inactivation of and , and loss of fusion expression. Whole-exome sequencing revealed minimal mutational and copy number heterogeneity, suggestive of "hard" clonal sweep. Patient-derived models generated from autopsy retained features consistent with small cell lung cancer and demonstrated resistance to ROS1 inhibitors. This case supports small cell transformation as a recurring resistance mechanism, and underscores the importance of elucidating its biology to expand therapeutic opportunities.