MAP2K1 mutation

This study highlights the aberrant activation of the mitogen-activated protein kinase (MAPK) pathway as another important mechanism of resistance to immunotherapy. This case provides direct clinical evidence that MEK1 E203K is involved in resistance to immune checkpoint inhibitors (ICIs). Furthermore, for the first time, the MEK inhibitor trametinib has shown promising results in treating tumors with this mutation.

To determine the sensitivity of KRAS or/and TP53-mutated cancer to KRAS, MEK1, or PLK1-targeted therapy, the inhibitors salirasib, trametinib, volasertib, and onvansertib were used in COAD cells with different KRAS and TP53 status. This treatment induced G1 and G2/M arrest, respectively, and showed the strongest synergistic effect in KRAS and TP53-mutated SW48 cells expressing mutant KRASG13D and transduced with TP53 shRNA, ultimately leading to apoptotic cell death. These effects are attributed to two-step inhibition mechanism that blocks the MAPK signaling pathway and disrupts mitosis in KRAS and TP53-mutated COAD cells.

One of these patients who had 100% homology began treatment with cladribine monotherapy and relapsed at 20 months, while the other 4 had initial treatment containing rituximab and have not relapsed. While those with BRAF V600 mutations might be candidates for BRAF inhibition, those with other BRAF mutations represent an opportunity for development of other specific inhibitors, not only for HCL/HCLv, but also for other malignancies. We believe more patients with HCL should be tested for non-V600E BRAF mutations.

Focal post-radiation necrosis at site of an irradiated brain metastasis developed 9 months after SRS and is successfully being treated with low-dose bevacizumab. This illustrates the utility of NGS profiles that include class-1/2 MAP2K1-mutations in patients with melanoma and other malignancies to provide valuable information on a potentially active individualized treatment option. A prospective clinical trial that further evaluates the efficacy of MEK-inhibitor therapies in MAP2K1-mutated tumors is justified.

The MEK1/2 inhibitors in combination with other kinase (BRaf/KRas/PI3K) inhibitors showed significant anti-proliferative activity. Other combination of MEK inhibitor with PD-1, DYRK1, EGFR, BTK and/or VEGF inhibitors etc. showed promising results in many cancers including colorectal, pancreatic, gastrointestinal, solid tumor, breast cancer, melanoma and multiple myeloma etc. The dual or multi-targeted approaches of these combinations showed better and precise treatment of patients with resistant cancer.

Preliminary results of the MatchMel study revealed a variety of molecular mutations in WT melanoma pts. NF1 alterations appeared to be linked with Hi-TMB, which was associated with response to immunotherapy.

P2, N=165, Recruiting, National Cancer Institute (NCI) | Trial completion date: Sep 2024 --> Oct 2028

We tracked ERV activation to the early induction of the transcription factor ELF3, which extensively bound and activated nonsilenced retroelements and synergized with IRF1 (interferon regulatory factor 1) in the activation of IFNs and IFN-stimulated genes. Trametinib-induced viral mimicry in PDAC may be exploited in the rational design of combination therapies in immuno-oncology.

Here we describe cell lines that exhibit doxycycline-dependent expression KRASG12V or BRAFV600E and harbour a stably integrated EGR1:EmGFP reporter gene that can be detected by flow cytometry, high-content microscopy or immunoblotting...Finally, substitution of EmGFP for a bacterial nitroreductase gene allowed KRASG12V or BRAFV600E to drive cell death in the presence of a pro-drug, which may allow selection of pathway inhibitors that promote survival. These cell lines should prove useful for cell-based screens to identify new regulators of KRAS- or BRAF-dependent ERK1/2 signalling (drug target discovery) as well as screening or triaging 'hits' from drug discovery screens.

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.

These findings warrant further studies of clinical applications of MEK1/2 inhibitors and KRAS as 'actionable target' of cisplatin-based chemotherapy for glioblastoma.

The mutations alter residue-level internal molecular correlations by differentially prioritizing different conformational states, delineating the various modes of MEK1 activation reminiscent of a gear-shifting mechanism. We define the molecular basis of conversion of this kinase from its inactive to its active state, connecting structure, dynamics, and function by delineating the energy landscape and conformational plasticity, thus augmenting our understanding of MEK1 regulation.