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1.
Gastric Cancer ; 27(3): 473-483, 2024 05.
Artigo em Inglês | MEDLINE | ID: mdl-38261067

RESUMO

BACKGROUND: Gastric cancer (GC) is the third leading cause of cancer-related death worldwide, with a poor prognosis for patients with advanced disease. Since the oncogenic role of KRAS mutants has been poorly investigated in GC, this study aims to biochemically and biologically characterize different KRAS-mutated models and unravel differences among KRAS mutants in response to therapy. METHODS: Taking advantage of a proprietary, molecularly annotated platform of more than 200 GC PDXs (patient-derived xenografts), we identified KRAS-mutated PDXs, from which primary cell lines were established. The different mutants were challenged with KRAS downstream inhibitors in in vitro and in vivo experiments. RESULTS: Cells expressing the rare KRAS A146T mutant showed lower RAS-GTP levels compared to those bearing the canonical G12/13D mutations. Nevertheless, all the KRAS-mutated cells displayed KRAS addiction. Surprisingly, even if the GEF SOS1 is considered critical for the activation of KRAS A146T mutants, its abrogation did not significantly affect cell viability. From the pharmacologic point of view, Trametinib monotherapy was more effective in A146T than in G12D-mutated models, suggesting a vulnerability to MEK inhibition. However, in the presence of mutations in the PI3K pathway, more frequently co-occurrent in A146T models, the association of Trametinib and the AKT inhibitor MK-2206 was required to optimize the response. CONCLUSION: A deeper genomic and biological characterization of KRAS mutants might sustain the development of more efficient and long-lasting therapeutic options for patients harbouring KRAS-driven GC.


Assuntos
Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Fosfatidilinositol 3-Quinases/metabolismo , Mutação , Inibidores de Proteínas Quinases/farmacologia , Linhagem Celular Tumoral
2.
Mol Oncol ; 18(6): 1355-1377, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38362705

RESUMO

Mutations in the RAS-RAF-MEK-ERK pathway are frequent alterations in cancer and RASopathies, and while RAS oncogene activation alone affects 19% of all patients and accounts for approximately 3.4 million new cases every year, less frequent alterations in the cascade's downstream effectors are also involved in cancer etiology. RAS proteins initiate the signaling cascade by promoting the dimerization of RAF kinases, which can act as oncoproteins as well: BRAFV600E is the most common oncogenic driver, mutated in the 8% of all malignancies. Research in this field led to the development of drugs that target the BRAFV600-like mutations (Class I), which are now utilized in clinics, but cause paradoxical activation of the pathway and resistance development. Furthermore, they are ineffective against non-BRAFV600E malignancies that dimerize and could be either RTK/RAS independent or dependent (Class II and III, respectively), which are still lacking an effective treatment. This review discusses the recent advances in anti-RAF therapies, including paradox breakers, dimer-inhibitors, immunotherapies, and other novel approaches, critically evaluating their efficacy in overcoming the therapeutic limitations, and their putative role in blocking the RAS pathway.


Assuntos
Neoplasias , Quinases raf , Proteínas ras , Humanos , Proteínas ras/metabolismo , Proteínas ras/genética , Quinases raf/metabolismo , Quinases raf/antagonistas & inibidores , Quinases raf/genética , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Animais , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Mutação , Proteínas Proto-Oncogênicas B-raf/metabolismo , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos , Terapia de Alvo Molecular
3.
Nat Commun ; 15(1): 7554, 2024 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-39215000

RESUMO

Selective KRASG12C inhibitors have been developed to covalently lock the oncogene in the inactive GDP-bound state. Two of these molecules, sotorasib and adagrasib, are approved for the treatment of adult patients with KRASG12C-mutated previously treated advanced non-small cell lung cancer. Drug treatment imposes selective pressures leading to the outgrowth of drug-resistant variants. Mass sequencing from patients' biopsies identified a number of acquired KRAS mutations -both in cis and in trans- in resistant tumors. We demonstrate here that disease progression in vivo can also occur due to adaptive mechanisms and increased KRAS-GTP loading. Using the preclinical tool tri-complex KRASG12C-selective covalent inhibitor, RMC-4998 (also known as RM-029), that targets the active GTP-bound (ON) state of the oncogene, we provide a proof-of-concept that the clinical stage KRASG12C(ON) inhibitor RMC-6291 alone or in combination with KRASG12C(OFF) drugs can be an alternative potential therapeutic strategy to circumvent resistance due to increased KRAS-GTP loading.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares , Proteínas Proto-Oncogênicas p21(ras) , Humanos , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/antagonistas & inibidores , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Animais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/patologia , Camundongos , Linhagem Celular Tumoral , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Mutação , Feminino , Ensaios Antitumorais Modelo de Xenoenxerto , Guanosina Trifosfato/metabolismo , Acetonitrilas , Piperazinas , Piridinas , Pirimidinas
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