JAK2 focal amplifications are associated with reduced survival and resistance to chemotherapy.
Major finding: JAK2 focal amplifications are associated with reduced survival and resistance to chemotherapy.
Clinical relevance: JAK2-specific inhibitors may be more effective against JAK2-amplified TNBCs than JAK1/2 inhibitors.
Impact: JAK2 amplification may serve as a biomarker for JAK2 dependence and guide TNBC treatment.
Triple-negative breast cancers (TNBC) have a poor survival rate and lack molecularly targeted therapies. To identify potential actionable alterations in TNBC, Balko, Schwarz, and colleagues analyzed targeted next-generation sequencing data from a cohort of 74 patients with triple-negative breast cancer following neoadjuvant chemotherapy (NAC). Approximately 10% of patients had amplifications in the JAK2 locus (9p24), which was associated with chemotherapy-resistant tumors, and reduced recurrence-free and overall survival. In two patients with available serial specimens, JAK2 copy number was normal in the diagnostic biopsies, elevated after NAC, and further elevated in metastatic recurrences, suggesting that JAK2 amplifications are enriched by chemotherapy. In TNBC cell lines with copy gain or amplification of JAK2, treatment with the JAK1/2 inhibitor ruxolitinib reduced phosphorylation of the downstream effectors STAT1 and STAT3, but not alternate JAK effectors STAT5 and STAT6. However, treatment with a JAK2 specific inhibitor (BSK805) had no effect on STAT3 phosphorylation, but did reduce STAT5 phosphorylation. Further, knockdown of JAK1, but not JAK2, reduced STAT3 phosphorylation, indicating that ruxolitinib treatment reducedSTAT1/STAT3 signaling through inhibition of JAK1, but not JAK2, whereas JAK2 knockdown reduced STAT5 phosphorylation. JAK2 signaling was essential for mammosphere formation; JAK2 knockdown or BSK805 treatment reduced mammosphere formation, whereas JAK1 knockdown or ruxolitinib treatment enhanced mammosphere formation. Moreover, in two TNBC xenografts with JAK2 amplification or copy gain, adding BSK805 to paclitaxel, a chemotherapeutic that spares cancer stem cell–like cells with tumor-initiating capacity, reduced tumor growth, suggesting that JAK2 inhibition suppressed chemotherapy-resistant tumor-initiating cells. Taken together, these results indicate that JAK2-amplified TNBCs are JAK2-dependent and more sensitive to specific JAK2 inhibitors than dual JAK1/2 inhibitors, suggesting investigation of JAK2 inhibitors in JAK2-amplified TNBC clinical trials.