1696O - Genomic profiling and molecular targeting of lung cancer brain metastases

Background

Approximately 40%-50% of cancer patients who develop brain metastases have lung cancer. There is very limited information on genetic signatures associated with lung cancer brain metastases and prior studies mostly included small cohorts of cases.

Methods

We analyzed a large collection of lung cancer cases (n = 47215 for all NSCLC; 29438 for lung adenocarcinoma LUAD) that underwent comprehensive genomic profiling (FoundationOne), and identified potential key genetic alterations involved in loco-regional lesions (Loco) vs extracranial metastases (EM) vs brain metastases. We then performed preclinical studies to determine their functional roles and downstream pathways.

Results

Compared to Loco, the top 3 most enriched genetic alterations were CDKN2A/2B loss and SMARCA4 mutation in EM, and amplifications of NFKBIA, RICTOR and KRAS in brain metastases. Previous studies suggested that the aberrant activation of PI3K/AKT/mTOR pathway was associated with the development of BM. We also found significantly more frequent alterations of the overall PI3K/AKT/mTOR pathway in the BM (Loco 13.0% vs EM 14.5% vs brain metastases 18.1%), which was primarily driven by the enrichment of RICTOR amplification (Loco 3.6% vs EM 6.2% vs brain metastases 8.6%) in LUAD. In vitro studies showed that both genetic and pharmacological ablation of RICTOR in RICTOR-amplified NSCLC cells significantly reduced migration and invasion, whereas upregulation of RICTOR facilitated these processes. Mechanistic studies suggested that RICTOR may regulate the metastatic process through modulating the AKT, MET, EMT and CXCL12 chemokine-CXCR4 pathways. In vivo studies in orthotopic mouse models further revealed that both inducible RICTOR knockdown (with doxycycline) and TAK228 (mTOR1/2 inhibitor) significantly inhibited lung cancer tumor growth and spread in the brain.

Conclusions

RICTOR amplification is the most enriched actionable genomic target in NSCLC brain metastases, and its ablation can lead to reduced local invasion and tumor progression in the brain. Our study provides a foundation for the development of RICTOR-targeted therapeutic strategies for the treatment and/or prevention of lung cancer brain metastases.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

ACS, ALA, LCFA/IASLC.

Disclosure

H. Cheng: Financial Interests, Personal, Advisory Role: Janssen; Financial Interests, Personal and Institutional, Research Grant: AstraZeneca; Financial Interests, Institutional, Sponsor/Funding: Genentech. E.S. Sokol: Financial Interests, Personal, Full or part-time Employment, Employee: Foundation Medicine; Financial Interests, Personal, Stocks/Shares, Stocks and stock options: Roche. J.S. Ross: Financial Interests, Personal, Full or part-time Employment, Medical Director: Foundation Medicine; Financial Interests, Personal, Stocks/Shares: Roche Holdings, Tango Therapeutics, Celsius Therapeutics. G.M. Frampton: Financial Interests, Personal, Other, Employee: Foundation Medicine; Financial Interests, Personal, Other, stocks/shareholder: Roche. A. Verma: Financial Interests, Personal, Research Grant: Prelude, BMS, GSK, Incyte, Medpacto, Curis and Eli Lilly; Financial Interests, Personal, Advisory Role: Stelexis, Bakx, Novartis, Acceleron and Celgene, Stelexis and Janssen; Financial Interests, Personal, Other, holds equity: Stelexis, Bakx and Throws Exception. B. Halmos: Financial Interests, Personal, Advisory Role: AstraZeneca Boehringer Ingelheim Veracyte Janssen Takeda Merck BMS Genentech Pfizer Eli-Lilly; Financial Interests, Personal and Institutional, Research Grant: Boehringer Ingelheim, AstraZeneca, Merck, BMS, Advaxis, Amgen, AbbVie, Daiichi Sankyo, Pfizer, GSK, Beigene, Janssen. All other authors have declared no conflicts of interest.