bims-pimaco 2023-05-14 papers

J Biol Chem. 2023 May 04. pii: S0021-9258(23)01817-3. [Epub ahead of print] 104789

The Ribosomal S6 Kinase 2 (RSK2)-SPRED2 complex regulates phosphorylation of RSK substrates and MAPK signaling.

Jocelyne Lopez, Daniel A Bonsor, Matthew J Sale, Anatoly Urisman, Jennifer L Mehalko, Miranda Cabanski-Dunning, Pau Castel, Dhirendra K Simanshu, Frank McCormick.

Sprouty-related EVH-1 domain-containing (SPRED) proteins are a family of proteins that negatively regulate the RAS-MAPK pathway, which is involved in the regulation of the mitogenic response and cell proliferation. However, the mechanism by which these proteins affect RAS-MAPK signaling has not been fully elucidated. Patients with mutations in SPRED give rise to unique disease phenotypes, thus we hypothesized that distinct interactions across SPRED proteins may account for alternative nodes of regulation. To characterize the SPRED interactome and evaluate how members of the SPRED family function through unique binding partners, here we performed affinity purification mass spectrometry. We identified 90-kDa ribosomal S6 kinase 2 (RSK2) as a specific interactor of SPRED2, but not SPRED1 or SPRED3. We identified that the N-terminal kinase domain of RSK2 mediates interaction between amino acids 123-201 of SPRED2. Using X-ray crystallography, we determined the structure of the SPRED2-RSK2 complex and identified the SPRED2 motif, F145A, as critical for interaction. Additionally, we found that formation of this interaction is regulated by MAPK signaling events. We also find that that this interaction between SPRED2 and RSK2 has functional consequences, whereby knockdown of SPRED2 resulted in increased phosphorylation of RSK substrates, YB1 and CREB. Furthermore, SPRED2 knockdown hindered phospho-RSK membrane and nuclear subcellular localization. Lastly, we report that disruption of the SPRED2-RSK complex has effects on RAS-MAPK signaling dynamics. Overall, our analysis reveals that members of the SPRED family have unique protein binding partners and describes the molecular and functional determinants of SPRED2-RSK2 complex dynamics.

Keywords: RASopathy; RSK2; SPRED2; neurofibromin

DOI: https://doi.org/10.1016/j.jbc.2023.104789

Curr Mol Med. 2023 May 09.

The mTOR Signaling Pathway and mTOR Inhibitors in Cancer: Next-generation Inhibitors and Approaches.

Murat Ihlamur, Busra Akgul, Yağmur Zengin, Şenay Vural Korkut, Kübra Kelleci, Emrah Şefik Abamor.

mTOR is a serine/threonine kinase that plays various roles in cell growth, proliferation, and metabolism. mTOR signaling in cancer becomes irregular. Therefore, drugs targeting mTOR have been developed. Although mTOR inhibitors rapamycin and rapamycin rapalogs (everolimus, rapamycin, temsirolimus, deforolimus, etc.) and new generation mTOR inhibitors (Rapalink, Dual PI3K/mTOR inhibitors, etc.) are used in cancer treatments, mTOR resistance mechanisms may inhibit the efficacy of these drugs. Therefore, new inhibition approaches are developed. Although these new inhibition approaches have not been widely investigated in cancer treatment, the use of nanoparticles has been evaluated as a new treatment option in a few types of cancer. This review outlines the functions of mTOR in the cancer process, its resistance mechanisms, and the efficiency of mTOR inhibitors in cancer treatment. Furthermore, it discusses the next-generation mTOR inhibitors and inhibition strategies created using nanoparticles. Since mTOR resistance mechanisms prevent the effects of mTOR inhibitors used in cancer treatments, new inhibition strategies should be developed. Inhibition approaches are created using nanoparticles, and one of them offers a promising treatment option with evidence supporting its effectiveness.

Keywords: cancer; mTOR; mTOR inhibitor; nanoparticles; next-generation inhibitors and approaches; resistance mechanisms

DOI: https://doi.org/10.2174/1566524023666230509161645

Cancer Sci. 2023 May 09.

D-1553: A novel KRASG12C inhibitor with potent and selective cellular and in vivo antitumor activity.

Zhe Shi, Jifang Weng, Haotao Niu, Hong Yang, Rongfeng Liu, Yan Weng, Qingqing Zhu, Yihong Zhang, Liangshan Tao, Zhenwu Wang, Seok Jae Huh, Yueheng Jiang, Hong Mei, Xing Dai, Ling Zhang, Yaolin Wang.

D-1553 is a small molecule inhibitor selectively targeting KRASG12C and currently in phase II clinical trials. Here, we report the preclinical data demonstrating antitumor activity of D-1553. Potency and specificity of D-1553 in inhibiting GDP-bound KRASG12C mutation were determined by thermal shift assay and KRASG12C -coupled nucleotide exchange assay. In vitro and in vivo antitumor activity of D-1553 alone or in combination with other therapies were evaluated in KRASG12C mutated cancer cells and xenograft models. D-1553 showed selective and potent activity against mutated GDP-bound KRASG12C protein. D-1553 selectively inhibited ERK phosphorylation in NCI-H358 cells harboring KRASG12C mutation. Compared to the KRAS WT and KRASG12D cell lines, D-1553 selectively inhibited cell viability in multiple KRASG12C cell lines, and the potency was slightly superior to sotorasib and adagrasib. In a panel of xenograft tumor models, D-1553, given orally, showed partial or complete tumor regression. The combination of D-1553 with chemotherapy, MEK inhibitor, or SHP2 inhibitor showed stronger potency on tumor growth inhibition or regression compared to D-1553 alone. These findings support the clinical evaluation of D-1553 as an efficacious drug candidate, both as a single agent or in combination, for patients with solid tumors harboring KRASG12C mutation.

Keywords: KRASG12C; inhibitor; mutation; solid tumor; targeted therapy

DOI: https://doi.org/10.1111/cas.15829