From basic researches to new achievements in therapeutic strategies of KRAS-driven cancers

Saliani, Mahsa; Jalal, Razieh; Ahmadian, Mohammad Réza

doi:10.20892/j.issn.2095-3941.2018.0530

Cited by 18 publications

(4 citation statements)

References 199 publications

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“…KRAS is a small GTPase that regulates many cellular responses through the MAPK, PI3K/AKT/mTOR, and RAS signaling pathways. Oncogenic activation of KRAS results in cell proliferation or immortality, angiogenesis, invasion, metastasis, changes in cellular energetics, and escape from apoptosis [ 18 ]. In patient 4, two TSGs, AMER1 and PIK3R1 were observed.…”

Section: Discussionmentioning

confidence: 99%

Clear Cell Adenocarcinoma of Urethra: Clinical and Pathologic Implications and Characterization of Molecular Aberrations

Song,

Lee,

Park

et al. 2024

Cancer Res Treat

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Purpose This study aimed to evaluate the molecular features of clear cell adenocarcinoma (CCA) of the urinary tract and investigate its pathogenic pathways and possible actionable targets.Materials and Methods We retrospectively collected the data of patients with CCA between January 1999 and December 2016; the data were independently reviewed by two pathologists. We selected five cases of urinary CCA, based on the clinicopathological features. We analyzed these five cases by whole exome sequencing (WES) and subsequent bioinformatics analyses to determine the mutational spectrum and possible pathogenic pathways.Results All patients were female with a median age of 62 years. All tumors were located in the urethra and showed aggressive behavior with disease progression. WES revealed several genetic alterations, including driver gene mutations (AMER1, ARID1A, CHD4, KMT2D, KRAS, PBRM1, and PIK3R1) and mutations in other important genes with tumor-suppressive and oncogenic roles (CSMD3, KEAP1, SMARCA4, and CACNA1D). We suggest putative pathogenic pathways (chromatin remodeling pathway, mitogen-activated protein kinase signaling pathway, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin pathway, and Wnt/β-catenin pathway) as candidates for targeted therapies.Conclusion Our findings shed light on the molecular background of this extremely rare tumor with poor prognosis and can help improve treatment options.

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Section: Discussionmentioning

confidence: 99%

Clear Cell Adenocarcinoma of Urethra: Clinical and Pathologic Implications and Characterization of Molecular Aberrations

Song,

Lee,

Park

et al. 2024

Cancer Res Treat

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“…The PI3K pathway is the second best-characterized RAS-effector and participates in the regulation of cell growth, cell cycle entry, cell survival, cytoskeleton reorganization, and metabolism. When active, PI3K transforms phosphatidylinositol (4,5)-bisphosphate (PIP2) into phosphatidylinositol (3,4,5)-trisphosphate (PIP3). PIP3 propagates intracellular signaling, which brings phosphoinositide-dependent kinase 1 (PDK1) and AKT to the membrane.…”

Section: Ras Downstream Effectors: Mapk/erk and Pi3k/akt/mtor Signali...mentioning

confidence: 99%

“…Thorough attempts to identify the mechanisms causing intracellular protein trafficking, alterations and KRAS signaling pathways have suggested several potential therapeutic approaches [3]. Furthermore, KRAS mutation is one of the most important predictive markers in determining resistance to epidermal growth factor receptor (EGFR) inhibitors [4].…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, KRAS mutation is one of the most important predictive markers in determining resistance to epidermal growth factor receptor (EGFR) inhibitors [4]. However, KRAS mutation is far from being simply an unfavorable predictive marker but is rather part of an evolving research process driven by an important clinical unmet need [3,4]. Nowadays, the chemotherapy options for the treatment of patients with advanced KRAS mutant microsatellite stable (MSS) CRC are cytotoxic doublets such as FOLFIRI, FOLFOX or FOLFOXIRI in combination with anti-vascular endothelial growth-factor (VEGF) drugs (i.e., bevacizumab and aflibercept) [5].…”

Section: Introductionmentioning

confidence: 99%

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KRAS: A Druggable Target in Colon Cancer Patients

Negri

Bottarelli

de’Angelis

et al. 2022

IJMS

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Mutations in KRAS are among the most frequent aberrations in cancer, including colon cancer. KRAS direct targeting is daunting due to KRAS protein resistance to small molecule inhibition. Moreover, its elevated affinity to cellular guanosine triphosphate (GTP) has made the design of specific drugs challenging. Indeed, KRAS was considered ‘undruggable’. KRASG12C is the most commonly mutated variant of KRAS in non-small cell lung cancer. Currently, the achievements obtained with covalent inhibitors of this variant have given the possibility to assess the best therapeutic approach to KRAS-driven tumors. Mutation-related biochemical assets and the tissue of origin are expected to influence responses to treatment. Further attempts to obtain mutant-specific KRAS (KRASG12C) switch-II covalent inhibitors are ongoing and the results are promising. Drugs targeted to block KRAS effector pathways could be combined with direct KRAS inhibitors, immunotherapy or T cell-targeting approaches in KRAS-mutant tumors. The development of valuable combination regimens will be essential against potential mechanisms of resistance that may arise during treatment.

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Structure-based inhibitor design of mutant RAS proteins—a paradigm shift

Nyíri

Koppány

Vértessy

2020

Cancer Metastasis Rev

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As a member of small GTPase family, KRAS protein is a key physiological modulator of various cellular activities including proliferation. However, mutations of KRAS present in numerous cancer types, most frequently in pancreatic (> 60%), colorectal (> 40%), and lung cancers, drive oncogenic processes through overactivation of proliferation. The G12C mutation of KRAS protein is especially abundant in the case of these types of malignancies. Despite its key importance in human disease, KRAS was assumed to be non-druggable for a long time since the protein seemingly lacks potential drug-binding pockets except the nucleotide-binding site, which is difficult to be targeted due to the high affinity of KRAS for both GDP and GTP. Recently, a new approach broke the ice and provided evidence that upon covalent targeting of the G12C mutant KRAS, a highly dynamic pocket was revealed. This novel targeting is especially important since it serves with an inherent solution for drug selectivity. Based on these results, various structure-based drug design projects have been launched to develop selective KRAS mutant inhibitors. In addition to the covalent modification strategy mostly applicable for G12C mutation, different innovative solutions have been suggested for the other frequently occurring oncogenic G12 mutants. Here we summarize the latest advances of this field, provide perspectives for novel approaches, and highlight the special properties of KRAS, which might issue some new challenges. Electronic supplementary material The online version of this article (10.1007/s10555-020-09914-6) contains supplementary material, which is available to authorized users.

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From basic researches to new achievements in therapeutic strategies of KRAS-driven cancers

Cited by 18 publications

References 199 publications

Clear Cell Adenocarcinoma of Urethra: Clinical and Pathologic Implications and Characterization of Molecular Aberrations

Clear Cell Adenocarcinoma of Urethra: Clinical and Pathologic Implications and Characterization of Molecular Aberrations

KRAS: A Druggable Target in Colon Cancer Patients

Structure-based inhibitor design of mutant RAS proteins—a paradigm shift

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