Response to crizotinib treatment for ROS1 p.H1999N mutation and secondary EGFR p.V774M mutation after drug...

Genetic fusion involving the ROS1 gene lead to the constitutive activation of its encoded tyrosine kinase, thereby acting as an oncogenic driver that promotes tumor cell proliferation. Numerous missense mutations in ROS1 are currently classified as variants of unknown significance, especially, mutations in kinase domain are crucial mediators of the resistance of ROS1 fusion-positive cancers to ROS1 tyrosine kinase inhibitors (TKIs). This study presents a rare case of a ROS1 p.H1999N mutation positive lung adenocarcinoma in a male patient, who has benefited from crizotinib treatment. Following 9 months of crizotinib treatment, chest computed tomography (CT) revealed disease progression. The pathological results of the second tissue biopsy indicated ROS1 p.H1999N mutation accompanied by EGFR p.V774M mutation. Subsequently, the patient received furmonertinib targeted therapy. This study highlights the importance of comprehensive genetic sequencing for clinical decision-making and underscores crizotinib' potential as the first-line target-therapy for ROS1 missense mutations tumors. Herein, we discuss the diagnostic challenges and the potential pathogenic mechanisms of this novel mutation. How to identify rare genes and translate their identification into clinical benefits is a worthwhile avenue for exploration in our future work.