PURPOSE

EGFR-tyrosine kinase inhibitor (TKI) is a standard first-line therapy for activated -mutated non-small cell lung cancer (NSCLC). Treatment options for patients with acquired EGFR-TKI resistance are limited. HER3 mediates EGFR-TKI resistance. Clinical trials of the HER3-targeting antibody-drug conjugate patritumab deruxtecan (HER3-DXd) demonstrated its anticancer activity in -mutated NSCLC; however, the mechanisms that regulate HER3 expression are unknown. This study was conducted with the aim to clarify the mechanisms underlying HER3 regulation in -mutated NSCLC tumors and explored the strategy for enhancing the anticancer activity of HER3-DXd in -mutated NSCLC.

EXPERIMENTAL DESIGN

Paired tumor samples were obtained from 48 patients with -mutated NSCLC treated with EGFR-TKI(s). HER3 expression was immunohistochemically quantified with H-score, and genomic alteration and transcriptomic signature were tested in tumors from pretreatment to post-EGFR-TKI resistance acquisition. The anticancer efficacy of HER3-DXd and osimertinib was evaluated in -mutated NSCLC cells.

RESULTS

We showed augmented HER3 expression in -mutated tumors with acquired EGFR-TKI resistance compared with paired pretreatment samples. RNA sequencing revealed that repressed PI3K/AKT/mTOR signaling was associated with HER3 augmentation, especially in tumors from patients who received continuous EGFR-TKI therapy. An study also showed that EGFR-TKI increased HER3 expression, repressed AKT phosphorylation in multiple -mutated cancers, and enhanced the anticancer activity of HER3-DXd.

CONCLUSIONS

Our findings help clarify the mechanisms of HER3 regulation in -mutated NSCLC tumors and highlight a rationale for combination therapy with HER3-DXd and EGFR-TKI in -mutated NSCLC.