- |||||||||| Lumakras (sotorasib) / Amgen
Review, Journal: How to manage KRAS G12C-mutated advanced non-small-cell lung cancer. (Pubmed Central) - Dec 2, 2022
Here, we review the current treatment landscape for patients with advanced NSCLCs harbouring a KRAS G12C mutation, including PD-(L) 1-based therapies and direct KRAS inhibitors as well as sequential treatment options. We also explore the possible mechanisms of resistance to KRAS inhibition and strategies to overcome resistance in patients with KRAS G12C-mutant NSCLC.
- |||||||||| Mekinist (trametinib) / Novartis, Lumakras (sotorasib) / Amgen
Journal: MEK inhibitor resistance in lung adenocarcinoma is associated with addiction to sustained ERK suppression. (Pubmed Central) - Nov 24, 2022
We suggest that the presence of mutant KRAS amplification in patients may identify those that may benefit from a "drug holiday" to circumvent drug resistance. These findings demonstrate the toxic potential of hyperactive ERK signaling and highlight potential therapeutic opportunities in patients bearing KRAS mutations.
- |||||||||| Lumakras (sotorasib) / Amgen
Journal: Oncogenic KRAS signaling drives evasion of innate immune surveillance in lung adenocarcinoma by activating CD47. (Pubmed Central) - Nov 23, 2022
Therapeutically, disruption of the KRAS-CD47 signaling axis with KRAS siRNA, the KRASG12C inhibitor AMG 510 or miR-34a mimic suppressed CD47 expression, enhanced the phagocytic capacity of macrophages and restored innate immune surveillance. Our results revealed a direct mechanistic link between active KRAS and innate immune evasion and identified CD47 as a major effector underlying KRAS-mediated immunosuppressive tumor microenvironment.
- |||||||||| Lumakras (sotorasib) / Amgen
Review, Journal, Tumor Mutational Burden, BRCA Biomarker, PARP Biomarker, IO biomarker: Are targeted therapies or immunotherapies effective in metastatic pancreatic adenocarcinoma? (Pubmed Central) - Nov 19, 2022
Chemotherapy using FOLFIRINOX (folinic acid, fluorouracil, irinotecan, oxaliplatin) or gemcitabine-nab-paclitaxel significantly improves life expectancy, but the median overall survival remains <1 year...Sotorasib shows signs of efficacy against tumors carrying the KRAS G12C mutation, and targeted therapies may also benefit patients with KRAS-wild-type PDAC...Other immunotherapies are emerging such as therapeutic vaccines or chimeric antigen receptor (CAR) T cells, but these strategies remain to be evaluated in large trials. In the future, treatment personalization based on tumor-derived organoids could potentially further improve treatment efficiency.
- |||||||||| adagrasib (MRTX849) / Mirati, Lumakras (sotorasib) / Amgen
Review, Journal, IO biomarker: Targeting KRASp.G12C Mutation in Advanced Non-Small Cell Lung Cancer: a New Era Has Begun. (Pubmed Central) - Nov 18, 2022
Promising efficacy and tolerability data emerging from the early phase CodeBreak trial have already supported the regulatory approval of sotorasib as first in class targeted treatment for the second-line treatment of KRASp.G12C-positive NSCLC population, following immunotherapy-based first-line therapies, while the randomized phase III CodeBreak 200 clinical study has recently confirmed a significant superiority of sotorasib over docetaxel in terms of progression-free survival and quality of life...The preliminary results of these trials have recently suggested a promising activity of SHP2 inhibitors in the front-line setting, while toxicity issues limited the concurrent administration of immune-checkpoint inhibitors and sotorasib. The identification of predictive genomic/immunological biomarkers will be crucial to understand how to optimally sequencing/combining different drugs and ultimately personalize treatment strategies under clinical investigation, to definitively increase the survival outcomes of KRASp.G12C mutant advanced NSCLC patients.
- |||||||||| Tagrisso (osimertinib) / AstraZeneca, Lumakras (sotorasib) / Amgen
Review, Journal: Reactivity of Covalent Fragments and Their Role in Fragment Based Drug Discovery. (Pubmed Central) - Nov 16, 2022
This review aims to discuss the requirements for an electrophilic fragment library and the importance of differing warhead reactivity. Successful case studies from the world of drug discovery are then be examined.
- |||||||||| adagrasib (MRTX849) / Mirati, RG6330 / Roche, Lumakras (sotorasib) / Amgen
Review, Journal, PD(L)-1 Biomarker, IO biomarker: KRAS in NSCLC: State of the Art and Future Perspectives. (Pubmed Central) - Nov 16, 2022
Ongoing trials are currently evaluating strategies for implementing efficacy and overcoming acquired resistance to these compounds. Finally, the efficacy of immune-checkpoint inhibitors still needs to be completely assessed and responses to anti-PD-1/PD-L1 agents may strongly depend on concomitant mutations.
- |||||||||| adagrasib (MRTX849) / Mirati, padnarsertib (KPT-9274) / Karyopharm, Lumakras (sotorasib) / Amgen
Novel Combination to Enhance the Antitumor Activity of KRASG12C Targeted Drugs (Coastal ABCD) - Nov 7, 2022 - Abstract #APAPancreatic2022APA_Pancreatic_126;
Background : KRASG12C inhibitors sotorasib and adagrasib have shown promising results in preclinical and clinical studies. This is the first study showing that KRASG12C inhibitors can synergize with PAK4 inhibitors resulting in improved antitumor activity.
- |||||||||| Lumakras (sotorasib) / Amgen
Review, Journal: Fragment-Based Drug Discovery - The Importance of High Quality Molecule Libraries. (Pubmed Central) - Nov 4, 2022
We highlight emerging chemical and computational technologies in FBDD and discuss strategies for optimising fragment hits. The impact of novel FBDD approaches is already being felt, with the recent approval of the covalent KRAS inhibitor sotorasib highlighting the utility of FBDD against targets that were long considered undruggable.
- |||||||||| Lumakras (sotorasib) / Amgen
Journal: PAK and PI3K pathway activation confers resistance to KRAS inhibitor sotorasib. (Pubmed Central) - Nov 3, 2022
The impact of novel FBDD approaches is already being felt, with the recent approval of the covalent KRAS inhibitor sotorasib highlighting the utility of FBDD against targets that were long considered undruggable. Our results indicate that the cell-matrix interaction-dependent activation of PAK mediates resistance to sotorasib through the activation of MAPK and PI3K pathways.
- |||||||||| Lumakras (sotorasib) / Amgen
Review, Journal, IO biomarker: Sotorasib: A Review in KRAS G12C Mutation-Positive Non-small Cell Lung Cancer. (Pubmed Central) - Nov 1, 2022
Sotorasib has a manageable tolerability profile, with permitted dose modifications to manage toxicity. In summary, sotorasib is a promising KRAS inhibitor that increases the available treatment options for patients with KRAS G12C mutation-positive NSCLC who were previously treated with platinum-based chemotherapy and/or immunotherapy.
- |||||||||| Lumakras (sotorasib) / Amgen
Review, Journal: Targeting KRAS in PDAC: A New Way to Cure It? (Pubmed Central) - Oct 28, 2022
The KRAS inhibitor sotorasib has been received by the FDA for the treatment of patients suffering from KRAS-driven cancers...Due to the high incidence of PDAC, developing KRAS inhibitors has become the focus of attention. Here, we review the clinical status of PDAC and recent research progress in targeting KRAS and discuss the potential applications.
- |||||||||| Lumakras (sotorasib) / Amgen
Journal: Chemical acylation of an acquired serine suppresses oncogenic signaling of K-Ras(G12S). (Pubmed Central) - Oct 28, 2022
The recently approved mutant selective small-molecule cysteine-reactive covalent inhibitor of the G12C mutant of K-Ras, sotorasib, provides a case in point...Our results provide a path to targeting a second somatic mutation in the oncogene KRAS by overcoming the weak nucleophilicity of an acquired serine residue. The chemistry we describe may serve as a basis for the selective targeting of other unactivated serines.
- |||||||||| Lumakras (sotorasib) / Amgen
Journal: An evaluation of sotorasib for the treatment of patients with non-small cell lung cancer with KRAS G12C mutations. (Pubmed Central) - Oct 28, 2022
Improvements in the clinical activity of KRAS inhibition will hinge on better understanding of resistance mechanisms, the development of broad-spectrum inhibitors with activity beyond G12C mutations, and combination therapy targeting multiple mediators of KRAS signaling and alternative pathways. From a regulatory perspective, sotorasib's development may, in time, prove to be an instructive example for early-phase clinical trialists and regulators focused on dose optimization.
- |||||||||| adagrasib (MRTX849) / Mirati, Lumakras (sotorasib) / Amgen
Journal: Identification of novel peptide inhibitors for the KRas-G12C variant to prevent oncogenic signaling. (Pubmed Central) - Oct 28, 2022
Our findings show that substitution of F3K, G11T, L8C, T14C, K13D, G11S, and G11P considerably enhances the binding affinity of the novel peptides, whereas F3K, G11T, L8C, and T14C peptides have higher stability and favorable binding to the altered peptides. Overall, our study paves the road for the development of potential therapeutic peptidomimetics that target the KRas-G12C complex and may inhibit the KRas and SOS complex from interacting.Communicated by Ramaswamy H. Sarma.
- |||||||||| Lumakras (sotorasib) / Amgen
Review, Journal, IO biomarker: Drugging KRAS: current perspectives and state-of-art review. (Pubmed Central) - Oct 27, 2022
Covalent inhibitors that block mutant KRAS G12C were successfully developed and sotorasib was the first KRAS G12C inhibitor to be approved, with several more in the pipeline...We also discuss the relationship between KRAS mutations and the tumour microenvironment, and therapeutic strategies to target KRAS. Finally, we review the current clinical evidence and ongoing clinical trials of novel agents targeting KRAS and shine light on resistance pathways known so far.
- |||||||||| Lumakras (sotorasib) / Amgen
A Highly Specific Digital PCR Assay for Detecting KRAS Mutations in Liquid Biopsy Samples () - Oct 24, 2022 - Abstract #AMP2022AMP_551;
Future studies will include clinical validation using serum obtained from patients known to harbor tumors with KRAS-G12C in collaboration with UCHealth. Our unique technology provides high performance, economy, and fast turnaround for more accessible results, leading to the promise for streamlined development of additional assays targeting other actionable mutations, like those in EGFR and BRAF, to aid oncologists in their care while also reducing the burden on patients.
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