HGF amplification

Chemotherapy is closely associated with changes in the molecular characteristics of HAS. After chemotherapy, at genomic and transcriptome level, many features were altered. These changes may be molecular markers of poor chemotherapeutic efficacy and play an important role in chemoresistance in HAS. In addition, ERBB2, FGFR2, MET and HGF gene amplification may be potential therapeutic targets for HAS.

Safety (adverse events, vital signs, ECG, hematology and biochemistry parameters) will also be reported. The first patient was enrolled onto the study on 28 October 2021.

Considering the predominant role of the MAPKs pathway on TKIs resistance, we generated NSCLC EGFR mutated cell lines resistant to TK inhibitors and evaluated the effect of edited miR-411-5p overexpression. We found that the edited miR-411-5p reduces proliferation and induces apoptosis, promoting EGFR TKIs response in NSCLC-resistant cells.

Although resistant cells were significantly more malignant, they retained sensitivity to Met kinase inhibition and acquired sensitivity to inhibition of ER stress signaling and cholesterol biosynthesis. Defining this mechanism reveals details of a rapidly acquired yet highly-orchestrated multisystem route of resistance to a selective molecularly-targeted agent and suggests strategies for early detection and effective intervention.

P1, N=50, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2023 --> Jan 2025 | Trial primary completion date: Dec 2023 --> Jan 2025

Current status The first patient was enrolled onto the study on 28 October 2021. At the early enrollment stage, during the biomarker pre-screening, approximately 28% of patients with PRCC who submitted a sample had eligible MET-driven status and of these patients with MET-driven PRCC, approximately 70% also met other eligibility criteria and were randomized.

MET-driven PRCC may respond to targeted agents. However, the presence of MET alterations did not appear to be predictive for outcomes in response to current therapies, which are not biomarker-driven, compared with MET-independent tumours.

This exploratory analysis highlights the potential role of NGS in improving our understanding of response and resistance to ceritinib. It also illustrates that ceritinib is active against almost all ALK resistance mutations found in ALKi-pretreated patients.

Other 3rd‑generation EGFR‑TKIs, such as abivertinib, rociletinib, nazartinib, olmutinib and alflutinib, are also at various stages of development. The mechanisms of acquired resistance mainly include an altered EGFR signaling pathway (EGFR tertiary mutations and amplification), activation of aberrant bypassing pathways (hepatocyte growth factor receptor amplification, human epidermal growth factor receptor 2 amplification and aberrant insulin‑like growth factor 1 receptor activation), downstream pathway activation (RAS/RAF/MEK/ERK and PI3K/AKT/mTOR) and histological/phenotypic transformations (SCLC transformation and epithelial‑mesenchymal transition). The combination of targeted therapies is a promising strategy to treat osimertinib‑resistant patients, and multiple clinical studies on novel combined therapies are ongoing.

P1, N=50, Recruiting, National Cancer Institute (NCI) | Trial completion date: Dec 2021 --> Dec 2023 | Trial primary completion date: Dec 2021 --> Dec 2023

P1, N=50, Recruiting, National Cancer Institute (NCI) | Suspended --> Recruiting

Accordingly, loss of mitochondrial membrane potential and apoptosis by multi-caspase activation were observed. In conclusion, these results show that the apoptotic effects of DPT on HCC827GR cells signify the potential of DPT to serve as an adjuvant anti-cancer drug by simultaneously inhibiting EGFR and MET.

P1, N=50, Suspended, National Cancer Institute (NCI) | Recruiting --> Suspended

P1, N=50, Recruiting, National Cancer Institute (NCI) | N=36 --> 50

P1; N=36; Recruiting; Sponsor: National Cancer Institute (NCI); Trial completion date: Dec 2020 --> Dec 2021

Two compounds were found to be possess sub-micromolar range inhibitory potential against EGFR (T790M), while one of the compound showed significant selective inhibitory potential against c-MET. Additionally, one compound was found to possess significant dual inhibitory potential against target kinases.

Treatments for patients (pts) with advanced/metastatic PRCC include those approved for clear cell RCC such as sunitinib or everolimus, however their activity in PRCC can be limited. MET alterations are frequent in advanced/metastatic PRCC and have potential to impact PFS and TTF, although our results show limited effect on OS. These data show that MET-driven tumours may not predict for poorer outcome vs MET-ind tumours and there is a need for suitable therapies for MET-driven PRCC. Research Funding: AstraZeneca

Although pt numbers and follow-up were limited, savolitinib demonstrated encouraging efficacy and an improved safety profile vs sunitinib, with fewer grade ≥3 AEs and fewer dose modifications required. Sunitinib performance was poorer than expected based on external retrospective data. Further investigation of savolitinib as a treatment option for MET-driven PRCC is warranted.

Both MAPK and PI3K pathways were involved in the three types of resistance mechanism-induced PD-L1 overexpression, whereas the NF-kappa B pathway was only involved in T790M-induced PD-L1 expression. HGF, MET-amplification, and EGFR-T790M upregulate PD-L1 expression in NSCLC and promote the immune escape of tumor cells through different mechanisms.