Combination therapy of adagrasib and abemaciclib in non-small cell lung cancer brain metastasis models genomically characterized by KRAS-G12C and homozygous loss of CDKN2A

Acta Neuropathologica Communications, Journal Year: 2025, Volume and Issue: 13(1)

Published: May 2, 2025

Abstract KRAS mutations are prevalent in brain metastases (BM) from non-small cell lung cancer (NSCLC). The activity of KRAS-G12C selective, brain-penetrant small molecule inhibitor adagrasib was recently demonstrated preclinical models BM and patients with carrying KRAS-G12C, leading to a clinical trial investigating this therapeutic approach. However, co-existing genomic drivers such as homozygous deletion CDKN2A/B may impact the utility adagrasib. We therefore explored combination therapy employing abemaciclib, CDK4/6 inhibitor, NSCLC driven by CDKN2A loss. In both adagrasib-resistant SW1573 cells adagrasib-responsive H2122 cells, abemaciclib slightly synergistic inhibiting viability vitro through targeting KRAS-ERK CDK4/6-Rb signaling pathways. Combination treatment necessary activate caspase 3/7-mediated apoptosis while alone comparably elicited cells. vivo, (75 mg/kg) twice daily (50 associated body weight loss (about 10%) mice bearing orthotopic derived or requiring 50% dose reduction some animals. Notably, treatment, but neither monotherapy, extended animal survival model. On other hand, monotherapy were similarly effective at prolonging survival, ineffective Pharmacokinetic studies confirmed properties agents revealed drug-drug interactions exposures plasma brains increased presence Immunohistochemistry on-target pharmacodynamic effects mice. Our work thus supports that can offer strategy genomically characterized

Language: Английский

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Immunotherapy in advanced, KRAS G12C-mutant non-small-cell lung cancer: current strategies and future directions

Therapeutic Advances in Medical Oncology, Journal Year: 2025, Volume and Issue: 17

Published: Jan. 1, 2025

Kirsten rat sarcoma ( KRAS ) mutations are present in up to 25% of non-small-cell lung cancer (NSCLC). G12C is the most common type mutation, representing approximately half cases -mutant NSCLC. Mutations activate RAF-MEK-ERK pathway, leading increased cell proliferation and survival. Recent advances drug development have led approval inhibitors sotorasib adagrasib. This review explores emerging therapeutic strategies G12C-mutant NSCLC, including dual checkpoint blockade combinations with inhibitors, a focus on setting advanced disease.

Language: Английский

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Targeting the Yin and Yang of KRASG12C

Trends in Molecular Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

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KRAS mutations in colorectal cancer: impacts on tumor microenvironment and therapeutic implications

Expert Opinion on Therapeutic Targets, Journal Year: 2025, Volume and Issue: unknown

Published: May 4, 2025

Despite decreasing trends in incidence, colorectal cancer (CRC) is still a major contributor to malignancy-related morbidities and mortalities. Groundbreaking advances immunotherapies targeted therapies benefit subset of CRC patients, with sub-optimal outcomes. Hence, there an unmet need design manufacture novel therapies, especially for advanced/metastatic disease. KRAS, the most highly mutated proto-oncogene across human malignancies, particularly pancreatic adenocarcinoma, non-small cell lung cancer, CRC, on-off switch governs several fundamental signaling cascades. KRAS mutations not only propel progression metastasis but also critically modulate responses therapies. We discuss impacts on CRC's tumor microenvironment describe strategies targeting its associated cascades mechanisms drug resistance. Drug development against has been challenging, mainly due structural properties (offering no appropriate binding site small molecules), critical functions wild-type non-cancerous cells, complex network downstream effector pathways (allowing malignant cells develop resistance). Pre-clinical early clinical data offer promises combining inhibitors

Language: Английский

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Therapeutic expression of RAS Degrader RRSP in Pancreatic Cancer via Nanocarrier-mediated mRNA delivery

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: June 14, 2024

ABSTRACT Therapeutic gene expression can address many of the challenges associated with controlled delivery intracellularly active biologics, such as enzymes that degrade RAS for treatment RAS-driven cancers. Here, we demonstrate an optimized synthetic nonviral platform composed poly(ethylene glycol)- b -poly(propylene sulfide) (PEG-PPS) block copolymers conjugated to a dendritic cationic peptide (PPDP2) nontoxic and therapeutic mRNA within human pancreatic cancer cells tumors. The naturally occurring bacterial enzyme RAS/RAP1-specific endopeptidase (RRSP) is potent degrader specifically targets all isoforms. Using PPDP2, rrsp -mRNA delivered resulting in RRSP protein expression, degradation RAS, loss cell proliferation. Further, tumors are reduced residual lacking detectable phosphorylated ERK. structural modeling, further noncatalytic RAS-binding domain provides high specificity RAS. These data support nanocarrier PPDP2 deliver tumor interrupt signaling system.

Language: Английский

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