Haiying Cheng, MD at Albert Einstein Cancer Center discusses an ASCO 2020 abstract entitled RICTOR amplification as a novel therapeutic target for lung cancer brain metastases
Around 20% to 50% of advanced lung cancer patients experience brain metastases correlated with debilitating cognitive dysfunction and a dismal prognosis. Very few studies investigating the genomics of brain metastases in lung cancer have been performed.
We studied extensively the occurrence of PI3K / AKT / RICTOR / mTOR pathway aberrations at primary and metastatic sites using an comprehensive database of NGS (FoundationOne) 11845 cases of lung adenocarcinoma. In orthotopic mouse models the possible functions of RICTOR amplification in brain metastasis development were studied both in vitro and in vivo.
PI3K / AKT / mTOR gene alterations were more common in metastatic sites compared with the primary tumor, with specific enrichment being noted in brain metastases. RICTOR amplification alone accounted for the observed higher incidence in both brain metastases (brain vs. primary: 9.73% vs. 3.50%; P = 2.6E-14; brain vs. other metastatic sites: 9.73% vs. 7.3%; P = 0.03) and other metastatic sites (other metastatic vs. primary: 7.3% vs. 3.5%; P = 10E-15), while PTEN, AKT1, PK3CA or mTOR genetic changes did not d In vitro, decreased cell migration and invasion was correlated with inducible RICTOR knockdown in H23 lung cancer cells (parental line with RICTOR amplification), whereas upregulation of RICTOR in HCC827 lung cancer cells (parental line with regular RICTOR copy numbers) was associated with an increase in both processes. These findings were verified using mTOR1/2 inhibitors with documented CNS penetration for pharmacological inhibition. In vivo, both inducible ablation of RICTOR and mTOR1/2 inhibitor TAK228 (Sapanisertinib) significantly inhibited brain tumor development in the lung cancer H23-R4-Luc, including a number of near-complete responses. Mechanistic studies indicate that through the AKT and CXCL12 chemokine-CXCR4 axis, RICTOR can control the brain metastasis process.
The first identified actionable target that is markedly enriched in brain metastases is RICTOR amplification. Our research offers a clear justification for developing therapeutic strategies targeted by RICTOR for the treatment and/or prevention of these major causes of morbidity and mortality of lung cancer.