- |||||||||| Krazati (adagrasib) / BMS, Lumakras (sotorasib) / Amgen
Journal: Advances and challenges in RAS signaling targeted therapy in leukemia. (Pubmed Central) - Jan 3, 2025
Despite these challenges, new approaches have generated optimism about targeting specific RAS mutations in an allele-dependent manner for cancer therapy, supporting by compelling biochemical and structural evidence, which inspires further exploration of RAS allele-specific vulnerabilities. This review will discuss recent advances and challenges in the development of therapies targeting RAS signaling, highlight emerging therapeutic strategies, and emphasize the importance of allele-specific approaches for leukemia treatment.
- |||||||||| Krazati (adagrasib) / BMS
Journal: Adagrasib in KRYSTAL-12 (Pubmed Central) - Dec 24, 2024
However, these results fall short of the 6-month PFS benchmark that had seemed achievable from what had been seen in phase 1 and 2 trials, mirroring similarly disappointing results from the CodeBreaK 200 trial wherein sotorasib, the first-in-class KRAS G12C inhibitor, also failed to meet the 6-month benchmark also thought to be possible when examining earlier trials. These results raise the question of adagrasib's true value in the second-line treatment setting and compel us to explore more potent novel therapies, combination therapies, and more as we seek to break the 6-month PFS barrier in the treatment of KRAS G12C mutant NSCLC.
- |||||||||| Lumakras (sotorasib) / Amgen
Preclinical, Journal: Preclinical Evaluation of [124I]-Sotorasib for the Imaging of Kirsten Rat Sarcoma G12C Mutant Tumors. (Pubmed Central) - Dec 19, 2024
Toward this goal, we have developed a sotorasib-based molecular agent for PET imaging and tested its efficacy in targeting tumor lesions with KRAS G12C mutations. Here, we describe the synthesis, in vitro and in vivo evaluation of an [124I]I-Sotorasib analog in targeting G12C mutant tumor lesions using PET imaging.
- |||||||||| Krazati (adagrasib) / BMS, Lumakras (sotorasib) / Amgen
Review, Journal, Metastases: KRAS mutations in advanced non-small cell lung cancer: From biology to novel therapeutic strategies. (Pubmed Central) - Dec 12, 2024
In this paper, we describe the role of KRAS mutations in NSCLC focusing on the clinical and molecular characteristics which potentially identify specific subtypes of NSCLC patients based on different KRAS mutations. We also provide an overview of the main clinical trials testing novel selective KRASG12C inhibitors as well as novel potential therapeutic strategies for NSCLC patients with non-G12C KRAS mutations.
- |||||||||| Journal: Reactivation of MAPK-SOX2 pathway confers ferroptosis sensitivity in KRASG12C inhibitor resistant tumors. (Pubmed Central) - Dec 9, 2024
The clinical success of KRASG12C inhibitors (G12Ci) including AMG510 and MRTX849 is limited by the eventual development of acquired resistance...We found the ferroptosis inducers including sorafenib and lapatinib stood out with an obvious growth inhibition in the G12Ci resistant cells...Ferroptosis induced by sulfasalazine (SAS) achieved obvious inhibition on the tumor growth of xenografts derived from AMG510-resistant KRASG12C-mutant cells. Collectively, our results suggest a novel therapeutic strategy to treat patients bearing G12Ci resistant cancers with ferroptosis inducers.
- |||||||||| RMC-7977 / Revolution Medicines
Pan-RAS Inhibitor RMC-7977 Overcomes Oncogenic RAS Signaling and Exerts Antileukemic Effects in CMML/AML Cells () - Dec 7, 2024 - Abstract #ASH2024ASH_7864;
Experiments evaluating the effects of RMC-7977 in cell line xenografts and additional patients' primary samples are ongoing and will be presented.Collectively, we have demonstrated that the pan-RAS inhibitor RCM-7977 is highly effective against RAS mutated CMML/AML cell lines arising from chronic myeloid neoplasms including CMML while sparing healthy hematopoietic stem and progenitor cells. This work provides the rationale to continue evaluating RAS inhibitors as a targeted therapy in RAS-mutated myeloid malignancies, which is a significant unmet need in the treatment of these conditions.
- |||||||||| Lumakras (sotorasib) / Amgen
Journal: USP7 deubiquitinates KRAS and promotes non-small cell lung cancer. (Pubmed Central) - Nov 30, 2024
Moreover, USP7 inhibitors suppress NSCLC cell proliferation, particularly in cells resistant to the KRAS-G12C inhibitor AMG510. In conclusion, our findings identify USP7 as a key deubiquitinase regulating RAS stability, and targeting USP7 is a promising strategy to counteract KRAS inhibitor resistance in NSCLC.
- |||||||||| Lumakras (sotorasib) / Amgen
Journal: FGTI-2734 Inhibits ERK Reactivation to Overcome Sotorasib Resistance in KRAS G12C Lung Cancer. (Pubmed Central) - Nov 28, 2024
Importantly, treatment of mice with FGTI-2734 inhibited sotorasib-induced ERK reactivation in KRAS G12C PDX, and treatment of mice with the combination of FGTI-2734 and sotorasib were also significantly more effective at suppressing in vivo the levels of P-ERK in sotorasib-resistant human KRAS G12C lung cancer xenografts as well as a PDX. Our findings provide a foundation for overcoming sotorasib resistance and potentially improving the treatment outcomes of KRAS G12C lung cancer.
- |||||||||| Krazati (adagrasib) / BMS, Lumakras (sotorasib) / Amgen
Journal, Adverse events: KRAS-G12 inhibitors in lung cancer therapy: unveiling the toxicity profile through a pharmacovigilance study. (Pubmed Central) - Nov 21, 2024
Our findings provide a foundation for overcoming sotorasib resistance and potentially improving the treatment outcomes of KRAS G12C lung cancer. Although most adverse effects are reversible, vigilance is warranted particularly for nephrotoxicity and hepatotoxicity during the administration of KRAS G12C inhibitors.
- |||||||||| Krazati (adagrasib) / BMS, divarasib (RG6330) / Roche, Lumakras (sotorasib) / Amgen
Review, Journal, Metastases: An updated overview of K-RAS G12C inhibitors in advanced stage non-small cell lung cancer. (Pubmed Central) - Nov 16, 2024
KRASG12C inhibitors sotorasib, adagrasib and the newer divarasib, has revolutionized treating patients harboring this mutation. Ongoing studies and future clinical trials will refine our understandings with the ultimate goal of improving survival and quality of life for patients with this challenging disease.
- |||||||||| Lumakras (sotorasib) / Amgen
Journal, Stroma: Stromal Reprogramming Optimizes KRAS-Specific Chemotherapy Inducing Antitumor Immunity in Pancreatic Cancer. (Pubmed Central) - Nov 14, 2024
The molecular mechanisms elucidated that the stroma intervention and KRAS signal pathway regulation reshaped the immunosuppression of PDAC and optimized cytotoxic T-cell-mediated antitumor immunity with sustained antitumor memory. Overall, our study provides a practical strategy with clinical translational promise for immunologically cold tumor PDAC treatment.
- |||||||||| Lumakras (sotorasib) / Amgen
Trial completion date: AMG 510 Ethnic Sensitivity Study (CodeBreaK 105). (clinicaltrials.gov) - Nov 14, 2024
P1, N=12, Active, not recruiting,
No abstract available Trial completion date: Dec 2024 --> Jun 2025
- |||||||||| Lumakras (sotorasib) / Amgen, docetaxel / Generic mfg.
Journal, HEOR, Real-world evidence, Real-world, Metastases: Real-world comparative effectiveness of sotorasib versus docetaxel in second line and beyond among patients with advanced non-small cell lung cancer (NSCLC). (Pubmed Central) - Nov 13, 2024
Patients in the US receiving sotorasib as 2L+ therapy for NSCLC in real-world clinical practice showed high adherence, TTNT comparable to progression-free survival observed in clinical trials, and HCC similar to those immediately prior to treatment demonstrating real-world benefits with no additional impact on healthcare resources with sotorasib. In this real-world comparative analysis of patients with pretreated KRAS G12C-mutated advanced NSCLC, sotorasib monotherapy demonstrated a longer median OS compared to docetaxel monotherapy or combination therapy.
- |||||||||| Krazati (adagrasib) / BMS, Lumakras (sotorasib) / Amgen
Review, Journal, Combination therapy: KRAS inhibitors in drug resistance and potential for combination therapy. (Pubmed Central) - Nov 7, 2024
Moreover, because KRASG12D and KRASG12V are more common than KRASG12C, focus must be placed on the therapeutic strategies for this type of patient, along with sustained efforts in research on these targets. In the present review, we try to focus on various strategies to overcome rapid resistance through the use of combinational treatments to improve the activity of KRASG12C inhibitors.
- |||||||||| Krazati (adagrasib) / BMS, Vectibix (panitumumab) / Amgen, Lumakras (sotorasib) / Amgen
Journal: KRAS and EGFR inhibitors: a new step in the management of colorectal cancer. (Pubmed Central) - Nov 6, 2024
In the present review, we try to focus on various strategies to overcome rapid resistance through the use of combinational treatments to improve the activity of KRASG12C inhibitors. No abstract available
- |||||||||| Krazati (adagrasib) / BMS
Journal: Adagrasib in KRYSTAL-12 (Pubmed Central) - Nov 6, 2024
Despite not reaching the 6-month mPFS benchmark, adagrasib offers significant clinical benefits, particularly for the management of CNS metastases. In this pros and cons debate, we argue that adagrasib has broken the KRAS G12C enigma code in NSCLC.
- |||||||||| Krazati (adagrasib) / BMS, Lumakras (sotorasib) / Amgen
Review, Journal: Peptide inhibitors targeting Ras and Ras-associated protein-protein interactions. (Pubmed Central) - Oct 27, 2024
Here we summarize different types of peptide inhibitors, including monocyclic peptides, bicyclic peptides, stapled peptides, and proteomimetic inhibitors, developed in recent years; emphasize the limits and achievements; and discuss the outlook and challenges associated with future research in peptide inhibitors. This review aims to provide a reference for the discovery of Ras peptide inhibitors.
- |||||||||| Vectibix (panitumumab) / Amgen, Lumakras (sotorasib) / Amgen, Mvasi (bevacizumab-awwb) / Daiichi Sankyo, Amgen, AbbVie
Trial completion date, Trial primary completion date: CodeBreaK 301: Study of Sotorasib, Panitumumab and FOLFIRI Versus FOLFIRI With or Without Bevacizumab-awwb in Treatment-na (clinicaltrials.gov) - Oct 18, 2024
P3, N=450, Recruiting,
Alongside, we further recommend to engineer this designed CAR in T-cells and evaluating their therapeutic efficiency in in vitro and in vivo studies in the near future. Trial completion date: Jan 2031 --> Apr 2031 | Trial primary completion date: Jun 2027 --> Sep 2027
- |||||||||| Lumakras (sotorasib) / Amgen
Journal: Modeling lung adenocarcinoma metastases using patient-derived organoids. (Pubmed Central) - Oct 17, 2024
Investigation of the response of KRASG12C PDOs to sotorasib demonstrates that the model can examine the efficacy of treatments to suppress metastasis and identify mechanisms of drug resistance. Finally, our PDO model cocultured with autologous peripheral blood mononuclear cells can potentially be used to determine the optimal immune-priming strategy for individual patients with LUAD.
- |||||||||| Lumakras (sotorasib) / Amgen
Trial completion date, Trial primary completion date, Monotherapy: CodeBreak101: Sotorasib Activity in Subjects With Advanced Solid Tumors With KRAS p.G12C Mutation (CodeBreak 101) (clinicaltrials.gov) - Oct 15, 2024
P1, N=1200, Recruiting,
Finally, our PDO model cocultured with autologous peripheral blood mononuclear cells can potentially be used to determine the optimal immune-priming strategy for individual patients with LUAD. Trial completion date: Mar 2028 --> Jun 2029 | Trial primary completion date: Sep 2025 --> Jan 2027
- |||||||||| Journal, Metabolomic study: Metabolic Response to Small Molecule Therapy in Colorectal Cancer Tracked with Raman Spectroscopy and Metabolomics. (Pubmed Central) - Oct 14, 2024
Cells treated with a combination of subtoxic doses of trametinib and BKM120, an inhibitor of the PI3K pathway, showed a synergistic response between the two pathways...RS metabolites were verified with mass spectrometry, and enrichment pathways were identified, including amino acid, purine, and nicotinate and nicotinamide metabolism that differentiated monotherapy from combination therapy. Our approach may ultimately be applicable to patient-derived primary cells and cultures of patient tumors to predict effective drugs for individualized care.
- |||||||||| Lumakras (sotorasib) / Amgen
Journal: The Retrofit: Lessons From Sotorasib's Dosing Conundrum. (Pubmed Central) - Oct 7, 2024
Accordingly, simultaneous inhibition of KRAS, MEK, and JAK2 could be an innovative therapeutic strategy against KRAS-mutant pancreatic cancer. No abstract available
- |||||||||| Novel dual MEK inhibitors for RAS-mutated colorectal cancer as a single agent or in combination with known therapies including aPD-1 (Exhibit Halls AB - George R. Brown Convention Center) - Oct 4, 2024 - Abstract #SITC2024SITC_1372;
In a CRC SW837 (KRAS-G12C, insensitive to Adagrasib) model, ABM-4218 showed synergic effect with Adagrasib, as well as the EGFR antibody Cetuximab...Conclusions In summary, A series of novel dual MEK inhibitors have been studied for the possible treatment of colorectal cancer by modulating the pERK level via the MEK1/2 kinase, which is the mechanism for the EGFR negative feedback loop. Good in vivo efficacies are observed in several CRC animal models, including the combination with immunotherapy.
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