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Characterization of the BH1406 non-small cell lung cancer (NSCLC) cell line carrying an activating SOS1 mutation
Gerhard Hamilton1, Sandra Stickler1, Mikhail Ermakov2
1Institute of Pharmacology, Medical University of Vienna, Vienna, Austria.
Background:
Approximately 30% of the non-small cell lung cancer (NSCLC) patients which harbor no recognizable oncogenic driver mutation are not eligible for targeted therapy. Functional drug screening of tumor cells helps to identify susceptible drug targets not recognized by gene panels for targeted mutation analysis. The aim of this study is to characterize the BH1406 cell line carrying an activating SOS1 mutation and to check its sensitivity to cognate inhibitors.
Methods:
The NSCLC cell line BH1406 was established from a pleural effusion and found to be sensitive to the SOS1 inhibitor BAY-293 in initial viability screenings. Since in a limited next-generation sequencing (NGS) lung cancer mutation panel no driver could be detected, the patient underwent chemotherapy with poor outcome. This cell line was further characterized by exome sequencing, SOS1 Western blotting, comparison of two-dimensional (2D) and three-dimensional (3D) chemosensitivity assays and phosphoprotein arrays.
Results:
In whole-exome sequencing (WES) the SOS1 mutation P481delinsLFFL, positioned near the known P478L activating mutation was detected. Besides BAY-293, BH1406 cells proved to be sensitive to the SOS1 inhibitors MRTX0902 and BI-3406. The sensitivity of BH1406 cells to BI-3406 was increased under 3D conditions compared to 2D cultures. Western blot phosphoprotein arrays revealed reduced phosphorylation of CREB, GSK3, CHK-2 and STAT3 in BH1406 by BAY-293 treatment in 2D culture. In 3D conditions, cells switched from GSK3α to elevated ERK1/2 signaling, again blocked by the SOS1 inhibitor BAY-293. Similar results were obtained for the SOS1 inhibitors MRTX0902 and BI3406. Additionally, the PI3K inhibitor dactolisib, the GSK-3 inhibitor BI-5521 as well as the bromodomain protein-directed PROTAC ARV-771 inhibited the growth of BH1406 cells significantly and showed synergistic interaction with BAY-293. Furthermore, Western blots demonstrated reduced expression of SOS1 and MYC proteins in response to BAY-293 treatment.
Conclusions:
The rare SOS1 P481delinsLFFL mutation in lung cancer may be targetable with corresponding inhibitors, alone or in combination with GSK3/PI3K/BET inhibitors. BH1406 cells represent a novel cellular model suitable for the molecular characterization of SOS1 druggability. Such rare oncogenic driver genes are not included in standard NGS panels and need to be detected by expanded assays like WES.
Insights
A novel non-small cell lung cancer (NSCLC) cell line, BH1406, with a rare SOS1 mutation is sensitive to SOS1 inhibitors. This discovery offers new targeted therapy options for NSCLC patients lacking common mutations.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Approximately 30% of non-small cell lung cancer (NSCLC) patients lack identifiable oncogenic driver mutations, limiting targeted therapy options.
- Functional drug screening of tumor cells can identify targets missed by standard genetic panels.
- The BH1406 cell line harbors an activating SOS1 mutation, presenting a potential target for novel therapies.
Purpose of the Study:
- To characterize the BH1406 NSCLC cell line with an activating SOS1 mutation.
- To evaluate the sensitivity of BH1406 cells to specific SOS1 inhibitors.
- To explore potential combination therapies for NSCLC with rare driver mutations.
Main Methods:
- Establishment and characterization of the BH1406 NSCLC cell line from pleural effusion.
- Whole-exome sequencing (WES) to identify the specific SOS1 mutation (P481delinsLFFL).
- In vitro chemosensitivity assays (2D and 3D cultures) and Western blot phosphoprotein arrays to assess drug responses and signaling pathways.
Main Results:
- The BH1406 cell line harbors the novel SOS1 P481delinsLFFL activating mutation.
- BH1406 cells demonstrated sensitivity to SOS1 inhibitors (BAY-293, MRTX0902, BI-3406), with enhanced sensitivity in 3D cultures.
- Inhibitors targeting PI3K, GSK-3, and BET proteins showed synergistic effects with SOS1 inhibitors, reducing cell growth and MYC expression.
Conclusions:
- The rare SOS1 P481delinsLFFL mutation in NSCLC is targetable with specific inhibitors.
- BH1406 cells serve as a valuable model for studying SOS1 druggability.
- Expanded genetic screening methods like WES are crucial for detecting rare oncogenic drivers in NSCLC patients.
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