Adagrasib in KRYSTAL-12 has Not Broken the KRAS G12C Enigma Code of the Unspoken 6-Month PFS Barrier in NSCLC DOI Creative Commons
Alexandria TM Lee, Misako Nagasaka

Lung Cancer Targets and Therapy, Journal Year: 2024, Volume and Issue: Volume 15, P. 169 - 176

Published: Dec. 1, 2024

Mutations in KRAS G12C are among the more common oncogenic driver mutations non-small cell lung cancer (NSCLC). In December 2022, US Food and Drug Administration (FDA) granted accelerated approval to adagrasib, a small molecule covalent inhibitor of G12C, for treatment patients with locally advanced or metastatic mutant NSCLC who received at least one prior systemic therapy based on promising results from phase 1 2 trials wherein adagrasib demonstrated median PFS 6.5 months. Results 3 KRYSTAL-12 trial were recently presented, showing benefit compared docetaxel, participants group demonstrating 5.5 months 3.8 docetaxel group. However, these fall short 6-month benchmark that had seemed achievable what been seen trials, mirroring similarly disappointing CodeBreaK 200 sotorasib, first-in-class inhibitor, also failed meet thought be possible when examining earlier trials. These raise question adagrasib's true value second-line setting compel us explore potent novel therapies, combination as we seek break barrier NSCLC.

Language: Английский

Targeting KRAS: from metabolic regulation to cancer treatment DOI Creative Commons
Yanyan Shi, Huiling Zheng, Tianzhen Wang

et al.

Molecular Cancer, Journal Year: 2025, Volume and Issue: 24(1)

Published: Jan. 11, 2025

The Kirsten rat sarcoma viral oncogene homolog (KRAS) protein plays a key pathogenic role in oncogenesis, cancer progression, and metastasis. Numerous studies have explored the of metabolic alterations KRAS-driven cancers, providing scientific rationale for targeting metabolism treatment. development KRAS-specific inhibitors has also garnered considerable attention, partly due to challenge acquired treatment resistance. Here, we review reprogramming glucose, glutamine, lipids regulated by oncogenic KRAS, with an emphasis on recent insights into relationship between changes mechanisms driven KRAS mutant related advances targeted therapy. We focus inhibitor discovery strategies colorectal, pancreatic, non-small cell lung cancer, including current clinical trials. Therefore, this provides overview understanding associated mutation therapeutic strategies, aiming facilitate challenges support investigation strategies.

Language: Английский

Citations

4
Oncogenic mutant KRAS inhibition through oxidation at cysteine 118 DOI Creative Commons
Maximilian Kramer‐Drauberg, Ettore Petrini, Alessia Mira

et al.

Molecular Oncology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 21, 2025

Language: Английский

Citations

0
Reducing pERKs to Break “RAS”istance to Sotorasib DOI
Steven G. Gray,

Derbrenn O'Connor,

Luciano Mutti

et al.

Journal of Thoracic Oncology, Journal Year: 2025, Volume and Issue: 20(3), P. 259 - 261

Published: March 1, 2025

Language: Английский

Citations

0
Targeting RAS and associated proteins DOI
Matthias Müller, Roger S. Goody, Daniel Rauh

et al.

Elsevier eBooks, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

Citations

0
Pancreatic Cancer: Pathogenesis and Clinical Studies DOI Creative Commons
Kexun Zhou,

Yingping Liu,

Chuanyun Tang

et al.

MedComm, Journal Year: 2025, Volume and Issue: 6(4)

Published: April 1, 2025

ABSTRACT Pancreatic cancer (PC) is a highly lethal malignancy, with pancreatic ductal adenocarcinoma (PDAC) being the most common and aggressive subtype, characterized by late diagnosis, progression, resistance to conventional therapies. Despite advances in understanding its pathogenesis, including identification of genetic mutations (e.g., KRAS, TP53, CDKN2A, SMAD4) dysregulated signaling pathways KRAS–MAPK, PI3K–AKT, TGF‐β pathways), effective therapeutic strategies remain limited. Current treatment modalities chemotherapy, targeted therapy, immunotherapy, radiotherapy, emerging therapies such as antibody–drug conjugates (ADCs), chimeric antigen receptor T (CAR‐T) cells, oncolytic viruses (OVs), vaccines, bispecific antibodies (BsAbs), face significant challenges. This review comprehensively summarizes these approaches, emphasizing their mechanisms, limitations, potential solutions, overcome bottlenecks. By integrating recent advancements outlining critical challenges, this aims provide insights into future directions guide development more for PC, specific focus on PDAC. Our work underscores urgency addressing unmet needs PDAC therapy highlights promising areas innovation field.

Language: Английский

Citations

0
Current status of KRAS G12C inhibitors in NSCLC and the potential for combination with anti-PD-(L)1 therapy: a systematic review DOI Creative Commons
Fan Zhang,

Banglu Wang,

Menghuan Wu

et al.

Frontiers in Immunology, Journal Year: 2025, Volume and Issue: 16

Published: April 15, 2025

In recent years, precision medicine for non-small cell lung cancer (NSCLC) has made significant strides, particularly with advancements in diagnostic and therapeutic technologies. Targeted 7therapies Anti-PD-(L)1 Therapies have emerged as vital treatment options, yet KRAS mutations, especially G12C, been historically difficult to address. Due the unique activation mechanism of G12C led development specific inhibitors, such AMG 510 MRTX849, which show promising potential. However, results from CodeBreaK 200 Phase III trial indicated that did not significantly improve overall survival compared docetaxel. Resistance after prolonged use inhibitors continues pose a challenge, prompting interest new drugs combination strategies. mutations can impair tumor-infiltrating T function create an immunosuppressive tumor microenvironment, making anti-PD-(L)1 therapies appealing. Preliminary data suggest these combinations may enhance both quality life, though safety concerns remain barrier. Ongoing research is crucial refine regimens identify suitable patient populations. This review focuses on monotherapy NSCLC, discussing major clinical trials future directions.

Language: Английский

Citations

0
Switch II pocket inhibitor allosterically freezes KRASG12Dnucleotide-binding site and arrests the GTPase cycle DOI
Haneul Kim, Geneviève M. C. Gasmi-Seabrook, Akira Uchida

et al.

Journal of Molecular Biology, Journal Year: 2025, Volume and Issue: unknown, P. 169162 - 169162

Published: April 1, 2025

Language: Английский

Citations

0
Breakthrough in RAS targeting with pan-RAS(ON) inhibitors RMC-7977 and RMC-6236 DOI Creative Commons
Panagiotis Filis, Dimitrios Salgkamis, Alexios Matikas

et al.

Drug Discovery Today, Journal Year: 2024, Volume and Issue: unknown, P. 104250 - 104250

Published: Nov. 1, 2024

Language: Английский

Citations

2
Discovery of BBO-8520, a first-in-class direct and covalent dual inhibitor of GTP-bound (ON) and GDP-bound (OFF) KRASG12C DOI Creative Commons
Anna E. Maciag,

James P. Stice,

Bin Wang

et al.

Cancer Discovery, Journal Year: 2024, Volume and Issue: 15(3), P. 578 - 594

Published: Dec. 6, 2024

Approved inhibitors of KRASG12C prevent oncogenic activation by sequestering the inactive, GDP-bound (OFF) form rather than directly binding and inhibiting active, GTP-bound (ON) form. This approach provides no direct target coverage active protein. Expectedly, adaptive resistance to (OFF)-only is observed in association with increased expression activity KRASG12C(ON). To provide optimal coverage, we have developed BBO-8520, a first-in-class, dual inhibitor KRASG12C(ON) forms. BBO-8520 binds Switch-II/Helix3 pocket, covalently modifies cysteine, disables effector exhibits potent signaling inhibition growth factor-activated states, which current demonstrate little measurable activity. In vivo, demonstrates rapid engagement signaling, resulting durable tumor regression multiple models, including those resistant KRASG12C(OFF)-only inhibitors. phase 1 clinical trials patients non-small cell lung cancer. Significance: first-in-class direct, small molecule covalent that engages inactive conformations. represents novel mechanism action allows for delays emergence seen clinic. See related commentary Zhou Westover, p. 455.

Language: Английский

Citations

2
KRAS mutations in advanced non-small cell lung cancer: From biology to novel therapeutic strategies DOI Creative Commons
Luigi Liguori, Fabio Salomone,

Angela Viggiano

et al.

Critical Reviews in Oncology/Hematology, Journal Year: 2024, Volume and Issue: 205, P. 104554 - 104554

Published: Nov. 9, 2024

Kristen rat sarcoma viral oncogene homolog (KRAS) mutations play a major role in the carcinogenesis of many types solid tumors including non-small cell lung cancer (NSCLC). Among KRAS mutations, p.G12C single-nucleotide variant (KRAS

Language: Английский

Citations

1