Targeting XPO1-mediated nuclear export potentiates ALK-TKI therapy in ALK+ non-small cell lung cancer

EML4-ALK fusion has emerged as a significant oncogenic driver in Non-Small Cell Lung Cancer (NSCLC), promoting abnormal cell proliferation and survival. Despite advances with specific tyrosine-kinase inhibitors (TKIs), resistance and relapse still pose significant challenges. Notably, patients with ALK+ NSCLC and co-occurring TP53 mutations experience poorer outcomes after treatment, underscoring an unmet medical need. To anticipate evolving resistance, it is essential to identify and target new vulnerabilities, both on-target and off-target. Exportin 1 (XPO1), a nuclear export protein involved in tumor growth and survival, has emerged as a promising target, and selective XPO1 inhibitors (XPO1i) have been developed. Analysis of the TCGA LUAD database reveals that patients with NSCLC exhibiting high XPO1 expression have poorer prognoses, highlighting XPO1 as a promising therapeutic target. In vitro and in vivo analyses using patient-derived cells, organoids, and xenograft models revealed that XPO1i enhances the antiproliferative and pro-apoptotic effects of ALK-TKIs. Synergy analysis confirmed a synergistic interaction between the drugs, with XPO1i inducing G1 arrest, p53 accumulation, and apoptosis even in p53-mutant settings. The combination therapy significantly inhibited tumor growth in resistant models, indicating its potential to overcome resistance mechanisms. These findings support the use of XPO1i and ALKTKI co-treatment as a promising strategy for patients with limited treatment options and suggest that early intervention with this combination may help delay or prevent the development of resistance in ALK+ NSCLC