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BRG1 (SMARCA4) Status Dictates the Response to EGFR Inhibitors in Wild-Type EGFR Non-Small Cell Lung Cancer
by
, , , ,
Rebaz Ahmed
1,2,†, 
Ranganayaki Muralidharan
1,‡,
Narsireddy Amreddy
1,§,
Akhil Srivastava
1,‖,
Meghna Mehta
3,
Janani Panneerselvam
1,¶,
Rodrigo Orlandini de Castro
4,
William L. Berry
5,6,
Susmita Ghosh
1,6
,
Murali Ragothaman
1,6,
Pawan Acharya
7,**,
Yan D. Zhao
6,7,
Roberto Jose Pezza
4,
Anupama Munshi
3,6,* and
Rajagopal Ramesh
1,2,6,* 1
Department of Pathology, The University of Oklahoma Health Sciences, Oklahoma City, OK 73104, USA
2
Graduate Program in Biomedical Sciences, The University of Oklahoma Health Sciences, Oklahoma City, OK 73104, USA
3
Department of Radiation Oncology, The University of Oklahoma Health Sciences, Oklahoma City, OK 73104, USA
4
Cell Cycle and Cancer Biology Program, Oklahoma Medical Research Foundation, Oklahoma City, OK 73104, USA
5
Department of Surgery, The University of Oklahoma Health Sciences, Oklahoma City, OK 73104, USA
6
OU Health Stephenson Cancer Center, The University of Oklahoma Health Sciences, Oklahoma City, OK 73104, USA
7
Biostatistics and Epidemiology, The University of Oklahoma Health Sciences, Oklahoma City, OK 73104, USA
*
Authors to whom correspondence should be addressed.
†
Current address: Kurdistan Institution for Strategic Studies and Scientific Research, 60 Gullabax, 335 Shorsh Street, Sulaymaniyah 46001, Kurdistan Region, Iraq.
‡
Current address: Lilly Corporate Center, 839 S. Delaware Street, Indianapolis, IN 46285, USA.
§
Current address: Cytovance, Oklahoma City, OK 73104, USA.
‖
Current address: Department of Pathology and Anatomical Sciences, University of Missouri School of Medicine, Columbia, MO 65212, USA.
¶
Current address: Kopra Bio, 135 Mississippi St, San Francisco, CA 94107, USA.
**
Current address: Department of Surgery, University of Alabama at Birmingham, 510 20th St, Suite #710,
Birmingham, AL 35233, USA.
Cancers 2026, 18(1), 62; https://doi.org/10.3390/cancers18010062
Submission received: 2 July 2025
/
Revised: 2 December 2025
/
Accepted: 9 December 2025
/
Published: 24 December 2025
(This article belongs to the Section Cancer Therapy)
Simple Summary
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.
Abstract
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.
Keywords:
lung cancer; EGFR; SMARCA4; BRG1; resistance; tyrosine kinase inhibitor; therapy
