temuterkib (LY3214996)

This work created a 12-gene signature based on NM, preliminary investigated immune infiltration in two risk categories, and discovered some possible anti-tumor medications. To sum up, our study findings offer fresh perspectives on the roles played by NM-associated genes in HCC development, prognosis, immunological response, and medication screening.

ERK1/2 inhibitors may serve as novel molecular-targeted drugs for treating leukemia with NRAS mutations.

P1/2, N=46, Active, not recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Dec 2024 --> Dec 2025

P1, N=42, Recruiting, Dana-Farber Cancer Institute | Trial completion date: Apr 2024 --> Apr 2025

Silvestrol inhibits the proliferation of NPC cells by targeting ERK phosphorylation. However, the inhibition of NPC cell migration by silvestrol was independent of the Raf-MEK-ERK pathway. RAP1A, HK2, and GADD45A may be potential targets for the action of silvestrol.

P1, N=50, Recruiting, Nader Sanai | Trial completion date: Feb 2024 --> Feb 2025 | Trial primary completion date: Dec 2023 --> Dec 2024

P2, N=52, Completed, Kimberly Perez, MD | Active, not recruiting --> Completed

P2, N=16, Terminated, Anita Turk | N=35 --> 16 | Trial completion date: Jul 2024 --> Aug 2023 | Recruiting --> Terminated | Trial primary completion date: Jun 2024 --> Aug 2023; Lack of efficacy.

P1/2, N=46, Active, not recruiting, M.D. Anderson Cancer Center | Phase classification: P1b/2 --> P1/2

Despite limited BBB permeability of LY321, combination LY321 and anti-PD-1 treatment amplifies extracranial immune responses that improve intracranial disease control, highlighting the role of extracranial tumors in driving intracranial response to treatment. Combined ERK and PD-1 inhibition is a promising therapeutic approach, worthy of further investigation for patients with melanoma BM.

P1, N=42, Recruiting, Dana-Farber Cancer Institute | N=30 --> 42

P1, N=80, Recruiting, OHSU Knight Cancer Institute | Trial completion date: Feb 2026 --> Feb 2028 | Trial primary completion date: Jun 2024 --> Jun 2026

P2, N=52, Active, not recruiting, Kimberly Perez, MD | Recruiting --> Active, not recruiting | Trial primary completion date: Nov 2023 --> Aug 2023

P1b/2, N=46, Active, not recruiting, M.D. Anderson Cancer Center | Recruiting --> Active, not recruiting | Trial completion date: Dec 2023 --> Dec 2024 | Trial primary completion date: Dec 2023 --> Dec 2024

These findings provide rationale for the clinical translation of CDK4/6 inhibitors alone and in combination with therapies targeting the RAS/MAPK pathway for the treatment of PNF and other peripheral nerve sheath tumors in persons with NF1.

The aim of this phase I/Ib trial is to assess safety and efficacy of treatment with SHP2 inhibitor RMC-4630 and ERK inhibitor LY3214996 in KRASm PDAC, non-small cell lung carcinoma (NSCLC) and colorectal carcinoma (CRC) patients. The RP2D has not been determined yet. Alterations in the PI3K/AKT/mTOR and the c-JUN pathways could be markers for drug resistance, which data are pending.

P1, N=30, Recruiting, Dana-Farber Cancer Institute | Trial primary completion date: Apr 2023 --> Apr 2024

As a result of our findings, combined inhibition of SHP2 and ERK is currently under investigation in a clinical trial (SHERPA, SHP2 and ERK inhibition in pancreatic cancer, NCT04916236), in patients with KRAS-mutant NSCLC, CRC and PDAC.

P1b/2, N=46, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2022 --> Dec 2023 | Trial primary completion date: Dec 2022 --> Dec 2023

We and others recently demonstrated that inhibition of the RAF-MEK-ERK pathway resulted in upregulated autophagy, and that dual treatment with the autophagy inhibitor hydroxychloroquine (HCQ)/chloroquine (CQ) and MEK or ERK inhibitors (MEKi, ERKi) synergistically blocked PDAC growth. These findings provided rationale for our initiation of Phase I/II clinical trials evaluating the combination of MEKi (binimetinib; NCT04132505) or ERKi (LY3214996; NCT04386057) with HCQ in PDAC...Importantly, when we inhibited MEK, with the clinical stage MEKi mirdametinib, and PIKfyve (with apilimod) together, we observed decreased MEKi-induced autophagic flux and synergistic impairment of PDAC cell proliferation...Furthermore, combining ERK-MAPK inhibition with vertical inhibition of autophagy improves the in vitro efficacy of this treatment strategy. Ongoing studies are aimed at delineating the mechanism underlying the synergy observed with anti-autophagy inhibitor combinations and further validation in more advanced preclinical models of PDAC.

P2, N=35, Recruiting, Anita Turk | Trial completion date: Sep 2023 --> Jul 2024 | Trial primary completion date: Jun 2023 --> Jun 2024

P1, N=210, Completed, Eli Lilly and Company | Active, not recruiting --> Completed | Trial completion date: Jul 2023 --> Oct 2022

Finally, we show evidence that F-fluorodeoxyglucose (FDG) positron emission tomography (PET) can be used to assess early drug responses in animal models. Based on these results, we will investigate this drug combination in the SHP2 and ERK inhibition in pancreatic cancer (SHERPA; ClinicalTrials.gov: NCT04916236) clinical trial, enrolling patients with KRAS-mutant PDAC.

LY3214996 (LY321) is a selective ERK 1/2 inhibitor that inhibits MAPK signaling and leads to regression of extracranial disease in preclinical models... Previous studies demonstrated that LY321 has minimal intracranial activity. However, we found that ERKi reduces intracranial tumor burden, with improved efficacy in combination with ICI in immunocompetent mice. Together, these data suggest that ERKi increases sensitivity to ICI therapy in pre-clinical brain metastasis models.

Using ERK1/2 and downstream kinase ELK1 reporter cell lines of lung cancer (H1299; NRAS), colon cancer (HCT-116; KRAS), neuroblastoma (SH-SY5Y), and leukemia (U937), we examined the relationship between ERK inhibition and drug-induced toxicity for five ERK inhibitors: SCH772984, ravoxertinib, LY3214996, ulixertinib, and VX-11e, as well as one MEK inhibitor, PD0325901. We also showed that cells that became resistant to the MEK1/2 inhibitor PD0325901 due to ERK1/2 reactivation remained sensitive to ERK1/2 inhibitor ulixertinib. Our data indicate that correlation of ERK inhibition with drug-induced toxicity in multiple cell lines may help to find more selective and effective ERK1/2 inhibitors.

P1, N=245, Active, not recruiting, Eli Lilly and Company | Trial completion date: Sep 2022 --> Jul 2023

The BMMSCs from patients with MBD (MBD‑MSC) or normal participants (Normal‑MSC) were isolated and induced to differentiation with dexamethasone. Furthermore, the application of LY3214996, the inhibitor of ERK also verified these outcomes. MiR-381-3p directly targeting FGF7 modulated the osteogenic differentiation via MEK/ERK signaling pathway in BMMSCs.

P1, N=55, Recruiting, The Netherlands Cancer Institute | Not yet recruiting --> Recruiting

P1, N=80, Recruiting, OHSU Knight Cancer Institute | N=40 --> 80 | Trial completion date: Feb 2025 --> Feb 2026 | Trial primary completion date: Jun 2022 --> Jun 2024

P1, N=50, Recruiting, Nader Sanai | Trial completion date: Feb 2022 --> Feb 2024 | Trial primary completion date: Dec 2021 --> Dec 2023

Key objectives of Phase 1b are to determine the safety and tolerability of LY3537982 monotherapy, and in combination with various agents: abemaciclib, erlotinib, cetuximab, an investigational ERK inhibitor (LY3214996), an investigational Aurora A kinase inhibitor (LY3295668), and an anti-PD1 antibody. Key exclusion criteria include presence of serious cardiac conditions, interstitial lung disease, symptomatic CNS malignancy, symptomatic CNS metastasis, or carcinomatous meningitis. The trial is currently enrolling patients (NCT04956640).

P1, N=55, Not yet recruiting, The Netherlands Cancer Institute | Trial completion date: Oct 2023 --> Jul 2024 | Initiation date: Oct 2021 --> Feb 2022 | Trial primary completion date: Oct 2023 --> Jan 2024

P1b/2, N=46, Recruiting, M.D. Anderson Cancer Center | Trial completion date: Dec 2021 --> Dec 2022 | Trial primary completion date: Dec 2021 --> Dec 2022

P2, N=35, Recruiting, Anita Turk | Trial completion date: Sep 2022 --> Sep 2023 | Trial primary completion date: Jun 2022 --> Jun 2023

Further research is necessary to elucidate under what genetic contexts abemaciclib, LY3214996 or the combination are most effective. Nonetheless, this work highlights that abemaciclib and LY3214996 should be further explored for CDKN2A or BRAF mutant BM.

P1, N=245, Active, not recruiting, Eli Lilly and Company | Trial completion date: Sep 2021 --> Sep 2022

FOXD1 promoted the proliferation and invasion of ESCC and was related to the ERK1/2 signaling pathway; ERK1/2 inhibitors (LY-3214996) reversed the biological function of FOXD1...In this study, micro- and nano-particles were used as carriers to construct Nanocapsules carrying miR-30a-5p mimics and miR-30a-5p inhibitor through self-assembly method, so as to realize an efficient Nanocapsules delivery system of miR-30a-5p to esophageal cancer cells. It provides insights into targeted drug therapy and the development of micro- and nano-particles carriers.

P2, N=35, Recruiting, Anita Turk | Trial primary completion date: Sep 2021 --> Jun 2022

P1a/1b, N=260, Recruiting, Eli Lilly and Company | Not yet recruiting --> Recruiting

P1a/1b, N=260, Not yet recruiting, Eli Lilly and Company