RAS‐targeted cancer therapy: Advances in drugging specific mutations

Liu, Cen; Ye, Danyang; Yang, Hongliu; Xu, Chong; Su, Zhijun; Li, Xia; Ding, Mei; Liu, Yonggang

doi:10.1002/mco2.285

Cited by 8 publications

(4 citation statements)

References 298 publications

(562 reference statements)

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“…Among them, RAS is a small GTPase that binds tightly to GTP with picomolar affinities. The mutants KRAS and NRAS are frequently found in cancers ( Liu et al, 2023 ). RAF is a serine/threonine kinase directly activated by RAS.…”

Section: Inhibitors Targeting Vegfr Downstream Signalingmentioning

confidence: 99%

Recent advances of anti-angiogenic inhibitors targeting VEGF/VEGFR axis

Wang,

Liu,

Broussy

et al. 2024

Front. Pharmacol.

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Vascular endothelial growth factors (VEGF), Vascular endothelial growth factor receptors (VEGFR) and their downstream signaling pathways are promising targets in anti-angiogenic therapy. They constitute a crucial system to regulate physiological and pathological angiogenesis. In the last 20 years, many anti-angiogenic drugs have been developed based on VEGF/VEGFR system to treat diverse cancers and retinopathies, and new drugs with improved properties continue to emerge at a fast rate. They consist of different molecular structures and characteristics, which enable them to inhibit the interaction of VEGF/VEGFR, to inhibit the activity of VEGFR tyrosine kinase (TK), or to inhibit VEGFR downstream signaling. In this paper, we reviewed the development of marketed anti-angiogenic drugs involved in the VEGF/VEGFR axis, as well as some important drug candidates in clinical trials. We discuss their mode of action, their clinical benefits, and the current challenges that will need to be addressed by the next-generation of anti-angiogenic drugs. We focus on the molecular structures and characteristics of each drug, including those approved only in China.

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Section: Inhibitors Targeting Vegfr Downstream Signalingmentioning

confidence: 99%

Recent advances of anti-angiogenic inhibitors targeting VEGF/VEGFR axis

Wang,

Liu,

Broussy

et al. 2024

Front. Pharmacol.

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“…In the first case, imatinib exerts its therapeutic effect by binding to the ATP-binding site of the hyper-activated mutated c-kit protein in exon 11, preventing its activity and inhibiting downstream signaling pathways [ 96 ]. In the second case, inhibitors (sotorasib and adagrasib) bind to the inactive GDP-bound form of KRAS p.G12C, locking it in an inactive state, unable to activate intracellular signals [ 97 ]. However, it is true that not all solid tumors with c-kit exon 11 or KRAS p.G12C mutations respond brilliantly to therapy.…”

Section: Measuring Tumor Heterogeneity: Challenges and Perspectivesmentioning

confidence: 99%

From Chaos to Opportunity: Decoding Cancer Heterogeneity for Enhanced Treatment Strategies

Ottaiano,

Ianniello,

Santorsola

et al. 2023

Biology

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Cancer manifests as a multifaceted disease, characterized by aberrant cellular proliferation, survival, migration, and invasion. Tumors exhibit variances across diverse dimensions, encompassing genetic, epigenetic, and transcriptional realms. This heterogeneity poses significant challenges in prognosis and treatment, affording tumors advantages through an increased propensity to accumulate mutations linked to immune system evasion and drug resistance. In this review, we offer insights into tumor heterogeneity as a crucial characteristic of cancer, exploring the difficulties associated with measuring and quantifying such heterogeneity from clinical and biological perspectives. By emphasizing the critical nature of understanding tumor heterogeneity, this work contributes to raising awareness about the importance of developing effective cancer therapies that target this distinct and elusive trait of cancer.

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“…These downstream effectors represent only a fraction of the intricate network of signaling pathways regulated by RAS. The complexity and diversity of RAS signaling indicate its fundamental importance in cellular physiology and its role in various diseases, particularly cancer ( 87 , 88 ).…”

Section: Inhibitors Of Kras and Associated Molecular Pathwaysmentioning

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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RAS‐targeted cancer therapy: Advances in drugging specific mutations

Cited by 8 publications

References 298 publications

Recent advances of anti-angiogenic inhibitors targeting VEGF/VEGFR axis

Recent advances of anti-angiogenic inhibitors targeting VEGF/VEGFR axis

From Chaos to Opportunity: Decoding Cancer Heterogeneity for Enhanced Treatment Strategies

Small molecular inhibitors for KRAS-mutant cancers

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