# BRG1 (SMARCA4) Status Dictates the Response to EGFR Inhibitors in Wild-Type EGFR Non-Small Cell Lung Cancer

## TL;DR

This study shows that the presence or absence of the BRG1 protein determines how well wild-type EGFR lung cancer cells respond to EGFR inhibitors.

## Contribution

The study reveals that BRG1 status is a novel biomarker for predicting response to EGFR-TKIs in wild-type EGFR lung cancer.

## Key findings

- BRG1-mutant cells were resistant to EGFR-TKIs, while restoring BRG1 reversed this resistance.
- Inhibiting AKT improved the effectiveness of EGFR-TKIs in BRG1-mutant cells.
- BRG1 status could help identify patients likely to benefit from EGFR-TKI or AKT inhibitor therapy.

## Abstract

The availability of EGFR-targeted tyrosine kinase inhibitors (TKIs) has increased the survival of non-small cell lung cancer patients harboring EGFR mutations. In contrast, only a small patient population that is wild-type for EGFR responds to EGFR-TKIs. This discrepancy in response to TKIs warrants investigation. Recent studies implicate a role for BRG1 in gene expression and resistance to therapy. The study objective was to investigate EGFR-TKI response in wild-type EGFR lung cancer cells that varied in BRG1 status. We identified that BRG1 mutation influenced the response to EGFR-TKIs in EGFR wild-type lung cancer cells both in vitro and in vivo. Additionally, EGFR–AKT complex formation was shown to contribute to EGFR-TKI resistance in BRG1-mutant A549 cells. Incorporating the AKT inhibitor (MK2206) in EGFR-TKI-resistant cells showed enhanced cytotoxicity in vitro. Our study findings demonstrate that screening for BRG1 status in wild-type EGFR lung cancer patients will aid in identifying individuals who are likely to benefit from EGFR-TKI therapy.

Background: Epidermal growth factor receptor (EGFR)-targeted tyrosine kinase inhibitors (TKIs) have exhibited efficacy in EGFR-mutant non-small cell lung cancer (NSCLC) patients. However, the response is modest in patients with wild-type (wt)-EGFR, and approximately 30–40% of patients develop TKI resistance. Recently, a role for BRG1 (SMARCA4) in regulating gene expression and its frequent alteration in various cancers, including NSCLC, has been reported. Yet, its specific function in response to EGFR-TKI therapy remains elusive. Herein, we investigated the role of BRG1 in EGFR-TKI response in vitro and in vivo using lung cancer models. Methods: In vitro, A549, H358, and HCC827 cell lines that varied in their EGFR and BRG1 status were assessed for response to EGFR-TKI upon overexpression or gene silencing of BRG1 through cell viability, cell migration, and Western blotting assays. In vivo, A549 and H358 tumor xenografts that overexpressed BRG1 or had BRG1 silenced were investigated for tumor growth response to EGFR-TKI. Results: EGFRwt/BRG1mt (A549) cells were resistant to TKI, and restoration of wt-BRG1 expression reverted them to TKI sensitivity both in vitro and in vivo. In contrast, silencing of BRG1wt in H358 cells showed a tendency toward TKI resistance. Additionally, wt-EGFR and pAKTSer473 protein complex formation in A549 cells was disrupted with an AKT inhibitor (MK2206), resulting in enhanced cytotoxicity in vitro. Conclusions: Our study demonstrates that EGFR-TKI response in wt-EGFR cells is dictated by BRG1 status. These findings propose screening of wt-EGFR NSCLC patients for BRG1 status for identifying individuals likely to benefit from EGFR-TKI therapy versus patients who will benefit from AKT inhibitor treatment.