Genetic alterations predict poor efficacy, outcomes and resistance to second-line osimertinib treatment in non-small cell lung cancer

Hao Bai; Lei Cheng; Wanting Liu; Wang-Yang Xu; Yingying Huo; Le Diao; Hao Ji; Liwen Xiong

doi:10.62347/VQNB4008

Genetic alterations predict poor efficacy, outcomes and resistance to second-line osimertinib treatment in non-small cell lung cancer

Am J Cancer Res. 2024 Jan 15;14(1):33-51. doi: 10.62347/VQNB4008. eCollection 2024.

Authors

Hao Bai¹, Lei Cheng¹, Wanting Liu¹, Wang-Yang Xu², Yingying Huo², Le Diao², Hao Ji^{3

4}, Liwen Xiong¹

Affiliations

¹ Department of Pulmonary and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine Shanghai 200030, P. R. China.
² Singlera Genomics Ltd. Shanghai 201203, P. R. China.
³ Department of Respiratory and Critical Care Medicine, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine Shanghai 200030, P. R. China.
⁴ Department of Healthcare Associated Infection Management, Shanghai Chest Hospital, Shanghai Jiao Tong University School of Medicine Shanghai 200030, P. R. China.

Abstract

The genetic heterogeneity of non-small cell lung cancer (NSCLC) may impact clinical response and outcomes to targeted therapies. In second-line osimertinib treatment for NSCLC, real-world data on genetic biomarkers for treatment efficacy and prognosis remain incomplete. This real-world study involved 68 NSCLC patients receiving first-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). All of these patients developed resistance, and 49 of them subsequently underwent second-line osimertinib treatment. A 639-gene DNA panel was employed to assess the impact of molecular alterations on treatment efficacy, clinical outcomes and resistance. The findings showed that the median progression-free survival (PFS) for second-line osimertinib therapy was 13.3 months. Genes alterations such as P21 (RAC1) activated kinase 5 (PAK5), RNA binding motif protein 10 (RBM10), and EPH receptor A3 (EPHA3) mutations were associated with significantly shorter PFS in osimertinib therapy. At multivariate analysis, they were all independent risk predictors of shorter PFS. Additionally, the median overall survival (OS) for osimertinib was 26.2 months. Glutamate ionotropic receptor NMDA type subunit 2A (GRIN2A), hepatocyte growth factor (HGF), and RBM10 mutations were significantly associated with poorer OS in osimertinib treatment. The multivariate analysis demonstrated that only RBM10 mutation emerged as an independent risk predictor of shorter OS. In vitro experiments showed that RBM10 mutations could promote the proliferation and migration ability of NSCLC cells and reduced cell apoptosis. The resistance mechanisms to osimertinib were heterogeneous. Histone cluster 1 H2B family member D (HIST1H2BD) acted as a novel resistance mechanism to osimertinib. Previously unreported HIST1H2BD mutations (p.K25Q and p.E36D) were detected in the NSCLC tissues. In vitro experiments confirmed that HIST1H2BD mutations led to resistance to osimertinib. In summary, we demonstrate that genetic biomarkers, such as PAK5, RBM10, and EPHA3, are independent predictors of PFS in second-line osimertinib treatment, with RBM10 emerging as an independent predictor of OS. Additionally, HIST1H2BD represents a novel resistance mutation to osimertinib. All of these findings offer valuable insights for making personalized treatment strategies for NSCLC patients.

Keywords: Clinical outcome; efficacy; genetic alteration; non-small cell lung cancer; resistance.