RICTOR amplification

This study clarified the genetic differences between OMM and NMM, and the first to report the frequent occurrence of RICTOR amplification in OMM. This analysis offers insights into the development of personalized therapeutics for OMM.

The increasing knowledge of molecular alterations in malignancies, including mutations and regulatory failures in the mTOR (mechanistic target of rapamycin) signaling pathway, highlights the importance of mTOR hyperactivity as a validated target in common and rare malignancies...Ongoing phase trials of new inhibitors and combination therapies are promising in advanced-stage patients selected by genetic alterations, molecular markers, and/or protein expression changes in the mTOR signaling pathway. Hopefully, the summarized results, our findings, and the suggested characterization of mTOR activity will support therapeutic decisions.

Here, we summarize recent advances that support an important role for Rictor and mTORC2 as potential therapeutic targets in the treatment of lung cancer. This is a traditional (narrative) review based on Pubmed and Google Scholar searches for the following keywords: Rictor, RICTOR amplification, mTORC2, Rictor complexes, lung cancer, metastasis, progression, mTOR inhibitors.

The newly described RICTOR-amplified entities could initiate further collaborative studies with larger cohorts to analyse the prevalence of RICTOR amplification in rare diseases. Finally, our and further work could help to improve and expand future therapeutic opportunities for mTOR-targeted therapies.

It is recommended to investigate mTOR profile activity in patients for whom mTOR inhibitor therapies are considered since the current first-generation mTOR inhibitors (rapamycin and analogues) may be ineffective in case of mTORC2 hyperactivity. Ongoing phase trials of new inhibitors and combination therapies are promising in advanced stage patients selected by molecular markers.

Our study showed a potential role of ctDNA in advanced gastric cancer, suggesting ctDNA’s sensitivity in detecting various druggable target genes. Investigation to reveal relationship between ctDNA and clinical outcomes is ongoing.

P2, N=5, Terminated, Shanghai Antengene Corporation Limited | N=48 --> 5 | Trial completion date: Sep 2022 --> May 2022 | Recruiting --> Terminated; Due to the low popularity of NGS testing in China and the small number of target subjects, our company decided to adjust the research and development strategy, terminate this study and not apply for new drug registration after careful consideration.

These results suggest that the presence of MUC5B mutation correlates with more potent anti-tumor efficacy of ATG-008, potentially serving as a positive predictive biomarker for patient enrichment that warrants further investigation in the clinic.

(1) Correlation between RICTOR amplification and Rictor membrane staining suggests that the latter can potentially be used as a surrogate marker to identify RICTOR-amplified lung SCCs. (2) Our findings also indicate that a significant proportion of PD-L1 negative lung SCCs harbor RICTOR amplification. Analysis of PD-L1 negative tumors using RICTOR FISH or Rictor IHC can help select patients who may benefit from mTORC2 inhibitor therapy.

P2, N=48, Recruiting, Shanghai Antengene Corporation Limited | Not yet recruiting --> Recruiting

Our results shed light on the molecular features that potentially drive lung cancer metastases. The distinct temporo-spatial pattern of disease progression revealed that lung cancer was prone to either late dissemination or indolent early lymph node metastases, leaving a potential time window to minimize metastases by early cancer detection.

Comparison of hand versus foot tumors revealed more frequent ulceration of SUM foot tumors, which correlated with more distal metastases and poorer overall survival. In summary, we find SUM are both clinically and molecularly distinct from acral melanoma, and our data suggest KIT, CDK4/6, and mTOR inhibitors may be particularly relevant and effective treatments for patients with SUM.

P2, N=48, Not yet recruiting, Shanghai Antengene Corporation Limited

Collectively, these data identify a mechanism for Rictor-driven tumor progression and provide further rationale for development of an mTORC2-specific inhibitor. Implications: RICTOR amplification drives NSCLC proliferation through formation of mTORC2, suggesting mTORC2-specific inhibition could be a beneficial therapeutic option.

Therefore, we suggest performing a detailed investigation of the mTOR profile before administering mTORC1 inhibitor therapy. Furthermore, our findings highlight that targeting the metabolic plasticity could be an alternative therapeutic approach.

To the best of the authors' knowledge, the current study is the first biomarker-driven umbrella study conducted in patients with recurrent SCLC. Although the current study demonstrated the limited clinical efficacy of monotherapy, novel biomarker approaches using other cell cycle inhibitor(s) or combinations warrant further investigation.

In conclusion, IHC expression of Rictor correlates highly with RICTOR amplification. Therefore, Rictor IHC can be used as a cost-effective method to select patients for RICTOR FISH and, potentially, for mTORC1/2 inhibitor therapy.

"In vivo, both inducible ablation of RICTOR and the mTOR1/2 inhibitor TAK228 (Sapanisertinib) significantly inhibited lung cancer H23-R4-Luc tumor growth in the brain, including a number of near complete responses...RICTOR amplification is the first identified actionable target that is markedly enriched in brain metastases. Our study provides a strong rationale for the development of RICTOR-targeted therapeutic strategies for the treatment and/or prevention of these major causes of lung cancer morbidity and mortality. Research Funding: U.S. National Institutes of Health, Other Foundation"

To date, two cases have received exome-supported targeted therapy: (1) a metastatic high grade serous ovarian cancer, HRD-high, treated with olaparib then cisplatin for a combined 15 months, and (2) a metastatic neuroendocrine rectal tumor with RICTOR amplification treated with everolimus starting in Dec 2016 until last follow-up in Sep 2019. WES and RNA-seq expanded detection of actionable biomarkers and oncogenic mutations, especially CNV, TMB/signatures, and HRD. Two cases have undergone exome-supported targeted treatment. We performed the first WES of a rare gastroblastoma, originally a CUP but reclassified by expanded fusion detection and RNA-seq.

"While Ki-67 expression was comparably low in IMA (range: 8-15%) and in primary CAD (range: 5-8%), we observed considerably higher proliferation rates in the non-colloid tumor compartment (16%) and metastases (72%) from CAD, as well as in the PEAD-group (36-71%). The overall tumor mutational burden was lowest in IMA (2.5 mutations per megabase), intermediate in CAD (5.8 mutations per megabase) and highest in PEAD (16.8 mutations per megabase). KRAS mutations were frequent in all three tumor subtypes, but TP53 mutations were mostly limited to PEAD. While chromosomal alterations were rare in IMA, we discovered MYC amplifications in three of four CAD. Comparing primary and metastatic CAD, we observed the acquisition of multiple mutations and chromosomal alterations. PEAD had a variety of chromosomal alterations, including two cases with RICTOR amplification. PD-L1 expression (20%, 50% and 80% of tumor cells) was limited to three PEAD samples, only. In conclusion, we provide..."