The Multi-Level Mechanism of Action of a Pan-Ras Inhibitor Explains its Antiproliferative Activity on Cetuximab-Resistant Cancer Cells

Tisi, Renata; Spinelli, Michela; Palmioli, Alessandro; Airoldi, Cristina; Cazzaniga, Paolo; Besozzi, Daniela; Nobile, Marco S.; Mazzoleni, Elisa; Arnhold, Simone; Gioia, Luca De; Grandori, Rita; Peri, Francesco; Vanoni, Marco; Sacco, Elena

doi:10.3389/fmolb.2021.625979

Cited by 9 publications

(7 citation statements)

References 59 publications

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“…According to a mathematical model of the RAS activation cycle, cmp4 when combined with cetuximab reduces the proliferation of cetuximab-resistant cancer cell lines. However, the affinity of cmp4 for RAS is unsatisfactory, and this limits its application as an ideal clinical drug ( 58 ).…”

Section: Evidence For Pan-ras Inhibitors In Ras-mutant Cancersmentioning

confidence: 99%

Small molecular inhibitors for KRAS-mutant cancers

Wu,

Song,

Cheng

et al. 2023

Front. Immunol.

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Three rat sarcoma (RAS) gene isoforms, KRAS, NRAS, and HRAS, constitute the most mutated family of small GTPases in cancer. While the development of targeted immunotherapies has led to a substantial improvement in the overall survival of patients with non-KRAS-mutant cancer, patients with RAS-mutant cancers have an overall poorer prognosis owing to the high aggressiveness of RAS-mutant tumors. KRAS mutations are strongly implicated in lung, pancreatic, and colorectal cancers. However, RAS mutations exhibit diverse patterns of isoforms, substitutions, and positions in different types of cancers. Despite being considered “undruggable”, recent advances in the use of allele-specific covalent inhibitors against the most common mutant form of RAS in non-small-cell lung cancer have led to the development of effective pharmacological interventions against RAS-mutant cancer. Sotorasib (AMG510) has been approved by the FDA as a second-line treatment for patients with KRAS-G12C mutant NSCLC who have received at least one prior systemic therapy. Other KRAS inhibitors are on the way to block KRAS-mutant cancers. In this review, we summarize the progress and promise of small-molecule inhibitors in clinical trials, including direct inhibitors of KRAS, pan-RAS inhibitors, inhibitors of RAS effector signaling, and immune checkpoint inhibitors or combinations with RAS inhibitors, to improve the prognosis of tumors with RAS mutations.

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Section: Evidence For Pan-ras Inhibitors In Ras-mutant Cancersmentioning

confidence: 99%

Small molecular inhibitors for KRAS-mutant cancers

Wu,

Song,

Cheng

et al. 2023

Front. Immunol.

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“…Although many effective treatments are available (192,193), there is also a very high percentage of patients who after a few months of treatment manifest resistance and tumor relapse (194) due to on-target mechanisms dependent on the coexistence of cell populations with different sensitivities to the drug (present before the treatment or acquired by selective pressure) (195) and/or offtarget mechanisms depending on the oncogenic activation of other genes and proteins (196,197). Other examples of drug resistance due to heterogeneity can be found in the study of Blaquier et al (198) and in other studies (192,194,199).…”

Section: Tumor Heterogeneity Drug Resistance and Clinical Outcomesmentioning

confidence: 99%

Preclinical Models and Emerging Technologies to Study the Effects of the Tumor Microenvironment on Cancer Heterogeneity and Drug Resistance

Adriani,

Cappello,

Lovisa

2023

Frontiers Research Topics

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Frontiers is more than just an open access publisher of scholarly articles: it is a pioneering approach to the world of academia, radically improving the way scholarly research is managed. The grand vision of Frontiers is a world where all people have an equal opportunity to seek, share and generate knowledge. Frontiers provides immediate and permanent online open access to all its publications, but this alone is not enough to realize our grand goals. Frontiers journal seriesThe Frontiers journal series is a multi-tier and interdisciplinary set of openaccess, online journals, promising a paradigm shift from the current review, selection and dissemination processes in academic publishing. All Frontiers journals are driven by researchers for researchers; therefore, they constitute a service to the scholarly community. At the same time, the Frontiers journal series operates on a revolutionary invention, the tiered publishing system, initially addressing specific communities of scholars, and gradually climbing up to broader public understanding, thus serving the interests of the lay society, too. Dedication to qualityEach Frontiers article is a landmark of the highest quality, thanks to genuinely collaborative interactions between authors and review editors, who include some of the world's best academicians. Research must be certified by peers before entering a stream of knowledge that may eventually reach the public -and shape society; therefore, Frontiers only applies the most rigorous and unbiased reviews. Frontiers revolutionizes research publishing by freely delivering the most outstanding research, evaluated with no bias from both the academic and social point of view. By applying the most advanced information technologies, Frontiers is catapulting scholarly publishing into a new generation. What are Frontiers Research Topics?Frontiers Research Topics are very popular trademarks of the Frontiers journals series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area.

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“…7 The development of cmp4-based drugs (pan-Ras inhibitors) is promising for combination therapies and cetuximab in reducing tumor cell proliferation. 8 Our previous study explored the importance of K-Ras binding site water molecules and dynamical changes of K-Ras mutant structures compared to the native model. 9,10 Another study focused on developing an engineered chimeric toxin, a pan-Ras biologic inhibitor for use in cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

“…For example, patients with K‐Ras mutations responded poorly to the anti‐EGFR drugs panitumumab and cetuximab 7 . The development of cmp4‐based drugs (pan‐Ras inhibitors) is promising for combination therapies and cetuximab in reducing tumor cell proliferation 8 . Our previous study explored the importance of K‐Ras binding site water molecules and dynamical changes of K‐Ras mutant structures compared to the native model 9,10 .…”

Section: Introductionmentioning

confidence: 99%

Identification of potential inhibitors, conformational dynamics, and mechanistic insights into mutant Kirsten rat sarcoma virus (G13D) driven cancers

Tayubi

2022

J of Cellular Biochemistry

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The mutations at the hotspot region of K‐Ras result in the progression of cancer types. Our study aimed to explore the small molecule inhibitors against the G13D mutant K‐Ras model with anti‐cancerous activity from food and drug administration (FDA)‐approved drug compounds. We implemented several computational strategies such as pharmacophore‐based virtual screening, molecular docking, absorption, distribution, metabolism and excretion features, and molecular simulation to ensure the identified hit compounds have potential efficacy against G13D K‐Ras. We found that the FDA‐approved compounds, namely, azelastine, dihydrocodeine, paroxetine, and tramadol, are potential candidates to inhibit the action of G13D mutant K‐Ras. All four compounds exhibited similar binding patterns of sotorasib, and a structural binding mechanism with significant hydrophobic contacts. The descriptor features from the QikProp of all four compounds are within allowable limits compared to sotorasib drug. Consequently, a molecular simulation result emphasized that the dihydrocodeine and tramadol exhibited less fluctuation, minimal basin, significant h‐bonds, and potent inhibition against G13D K‐Ras. As a result, the current research identifies prospective K‐Ras inhibitors that could be further improved with biochemical analysis for precision medicine against K‐Ras‐driven cancers.

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The Multi-Level Mechanism of Action of a Pan-Ras Inhibitor Explains its Antiproliferative Activity on Cetuximab-Resistant Cancer Cells

Cited by 9 publications

References 59 publications

Small molecular inhibitors for KRAS-mutant cancers

Small molecular inhibitors for KRAS-mutant cancers

Preclinical Models and Emerging Technologies to Study the Effects of the Tumor Microenvironment on Cancer Heterogeneity and Drug Resistance

Identification of potential inhibitors, conformational dynamics, and mechanistic insights into mutant Kirsten rat sarcoma virus (G13D) driven cancers

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