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A Combinatorial Strategy For Treating Kras-Mutant Lung Cancer

Di: Henry

Therapeutic targeting of KRAS-mutant lung adenocarcinoma represents a major goal of clinical oncology. KRAS itself has proved difficult to inhibit, and the effectiveness of agents that target key KRAS effectors has been thwarted by activation of compensatory or parallel pathways that limit their efficacy as single agents. Here we take a systematic approach towards identifying

Treatment in KRAS-mutant non-small cell lung cancer | CMAR

Finally, we showed that this combinatorial strategy, by targeting the synthetic lethal partners of the oncogene KRAS, is a potential novel and efficacious treatment of KRAS -mutant cancers.

In KRAS mutant lung cancer cell lines, KRAS G12D primarily activates the PI3K/AKT and MAPK pathways, while KRAS G12C and G12V mutants preferentially activate Ral signaling and demonstrate reduced activation of the PI3K pathway in

Combinatorial strategies to target RAS-driven cancers

Manchado, E. et al. A combinatorial strategy for treating KRAS-mutant lung cancer. Nature 534, 647–651 (2016). This study, through analysis of a trametinib-anchored short hairpin RNA knockdown activation of STAT3 screen, establishes FGFR1-mediated reactivation of the RAS pathway as resistance mechanism to MEK inhibition in KRAS-mutant lung cancer and highlights the tissue specificity

KRAS is the most common oncogene to be mutated in lung cancer, and therapeutics directly targeting KRAS have proven to be challenging. The mutations of KRAS are associated with poor prognosis, and resistance to both adjuvant therapy and targeted EGFR TKI. EGFR TKIs provide significant clinical benefit for patients whose tumors bear EGFR mutations. 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 in preclinical models of BM and patients with BM carrying KRAS-G12C, leading to a clinical trial investigating this therapeutic approach. However, co Therapeutic targeting of KRAS-mutant lung adenocarcinoma represents a major goal of clinical oncology. KRAS itself has proved difficult to inhibit, and the effectiveness of agents that target key KRAS effectors has been thwarted by activation of compensatory or parallel pathways that limit their efficacy as single agents. Here we take a systematic approach towards identifying

Background Kirsten rat sarcoma (KRAS) mutations are somatic variants in lung adenocarcinoma. One of the most prevalent mutations, G12C, has led to the clinical approval of targeted inhibitors for advanced stages in lung cancer. Research has increasingly focused on the efficacy of combination therapies that target multiple tumorigenic pathways. Cases harboring Numerous combinatorial therapies involving KRAS inhibitors are in clinical trials aiming to overcome therapy resistance. Additionally, other mutant-specific inhibitors (e.g., KRAS G12D), as well as pan-KRAS inhibitors or RAS (ON) multiselective inhibitors, are entering clinical trials and demonstrating promising results.

  • Combinatorial strategies to target RAS-driven cancers
  • Drug Combinatorial Therapies for the Treatment of KRAS Mutated Lung Cancers
  • New Horizons in KRAS-Mutant Lung Cancer: Dawn After Darkness

The first successes occurred with allele-specific targeting of KRAS p.Gly12Cys (G12C) in non-small cell lung cancer, resulting in regulatory approval of two agents—sotorasib and adagrasib.

Therapeutic targeting of KRAS-mutant lung adenocarcinoma represents a major goal of clinical oncology. KRAS itself has proved difficult to inhibit, and the effectiveness of agents that target key KRAS effectors has been thwarted by activation of compensatory or parallel pathways that limit their efficacy as single agents. Here we take a systematic approach towards identifying Populations of KRAS (G12C)-mutant cancer cells can rapidly bypass the effects of treatment 534 7609 647 with KRAS (G12C) inhibitors because a subset of cells escapes drug-induced quiescence by producing new Older research outputs will score higher simply because they’ve had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 354,481 tracked outputs that were published within six weeks on either side of this one in any source. This one has done particularly well, scoring higher than 96% of its contemporaries .

Innovative therapeutic agents have significantly improved outcomes, with an acceptable safety profile, in a substantial proportion of non-small cell lung cancer (NSCLC) patients in whom the malignant phenotype of the disease is determined by oncogenic molecular alterations. However, the benefit seen with these treatment models has not translated well to Abstract Therapeutic targeting of KRAS-mutant lung adenocarcinoma represents a major goal of clinical oncology. KRAS itself has proved difficult to inhibit, and the effectiveness of agents that target key KRAS effectors has been thwarted by activation of compensatory or parallel pathways that limit their efficacy as single agents. Here we take a systematic approach

Pairing SHP2i with a mutant-selective agent might be a more promising therapeutic strategy, as it would limit the toxicity of “vertical” pathway inhibition seen with MEKi/SHP2i combinations. Previous studies showed that after MEKi-treatment of KRAS -mutant cancer cells, SHP2is prevent MEK/ERK pathway reactivation at the level of SOS1/2 [13, 18]. With the continuous emergence of novel therapeutics and ongoing exploration of combination therapy regimens, the efficacy of KRAS inhibitors in cancer treatment is expected to further improve, offering a beacon of hope for cancer patients harboring KRAS gene mutations.

Intrinsic resistance to MEK inhibition in KRAS mutant lung and colon cancer through transcriptional induction of ERBB3. Therapeutic targeting of KRAS-mutant lung adenocarcinoma represents a major goal of clinical oncology. KRAS itself has proved difficult to inhibit, and the effectiveness of agents that target key KRAS effectors has been thwarted by activation of compensatory or parallel pathways EGFR TKIs that limit their efficacy as single agents. Here we take a systematic approach towards identifying Importantly, KRAS-mutant lung Cancer cells and patients’ tumours treated with trametinib show an increase in FRS2 phosphorylation, a biomarker of FGFR activation; this increase is abolished by FGFR1 inhibition and correlates with sensitivity to trametinib and FGFR Inhibitor combinations.

Therapeutic targeting of KRAS-mutant lung adenocarcinoma represents a major goal of clinical oncology. KRAS itself has proved difficult to inhibit, and the effectiveness of agents that target key KRAS effectors has been thwarted by activation of compensatory or parallel pathways that limit their efficacy as single agents. Here we take a systematic approach towards identifying Importantly, KRAS-mutant lung cancer cells and patients’ tumours treated with trametinib KRAS inhibitors or RAS show an increase in FRS2 phosphorylation, a biomarker of FGFR activation; this increase is abolished by FGFR1 inhibition and correlates with sensitivity to trametinib and FGFR inhibitor combinations. Others have demonstrated previously that FGFR1 can mediate adaptive resistance to trametinib in KRAS-mutant lung cancer and MEK inhibition led to autocrine activation of STAT3 via the FGF receptor and JAK kinases in EGFR mutant lung cancer [12, 25].

Abstract Therapeutic targeting of KRAS-mutant lung adenocarcinoma represents a major goal of clinical oncology. KRAS itself has proved difficult to inhibit, and the effectiveness of agents that target key KRAS effectors has been thwarted by activation of compensatory or parallel pathways that limit their efficacy as single agents. Here we take a systematic approach towards Abstract Mutant Kirsten rat sarcoma viral oncogene homolog (KRAS) is now a drugable oncogenic driver and the KRAS G12C variant responds clinically to sotorasib and adagrasib that covalently block the cysteine of the active center and inhibit downstream signaling and proliferation. Unfortunately, progression-free survival (PFS) of lung cancer patients is only Finally, we showed that this combinatorial strategy, by targeting the synthetic lethal partners of the oncogene KRAS, is a potential novel and efficacious treatment of KRAS -mutant cancers.

Collectively, our results demonstrate that genetic or pharmacological inhibition of YAP can increase sensitivity to LY3009120 in pancreatic cancer through blocking compensatory activation of a parallel AKT signal pathway, thereby validating a combinatorial approach for treating KRAS-mutant pancreatic cancer. This study provided the mechanistic support for combinatorial treatment (MEK plus histone deacetylase inhibitors) for KRAS -mutant lung cancer, and, again, highlighted the importance of stratification of epithelial and mesenchymal subsets in decision-making for treating KRAS -mutant lung cancer. As reported in the paper entitled „Suppression of KRas-mutant cancer through the combined inhibition of KRAS with PLK1 and ROCK“ in Nature Communications, we performed a synthetic lethal screening with a combinatorial strategy on a panel of clinical drugs; we found that combined inhibition of polo-like kinase 1 and RhoA/Rho kinase

Numerous combinatorial therapies involving KRAS inhibitors are in clinical trials aiming to overcome therapy resistance. Additionally, other mutant-specific inhibitors (e.g., KRAS G12D), as well as pan-KRAS inhibitors or RAS (ON) multiselective inhibitors, are entering clinical trials and demonstrating promising results.

Activating mutations in KRAS are highly prevalent in solid tumours and are frequently found in 35% of lung, 45% of colorectal, and up to 90% of pancreatic cancers. Mutated KRAS is a prognostic factor for disease-free survival (DFS) and overall survival (OS) in NSCLC and is Cases harboring Numerous combinatorial therapies associated with a more aggressive clinical phenotype, highlighting the need for KRAS Published 2016 View Full Article Home Publications Publication Search Publication Details Title A combinatorial strategy for treating KRAS-mutant lung cancer Authors Keywords – Journal

Therapeutic targeting of KRAS-mutant lung adenocarcinoma represents a major goal of clinical oncology. KRAS itself has proved difficult to inhibit, and the effectiveness of agents that target key KRAS effectors KRAS mutant has been thwarted by activation of compensatory or Sci-Hub | A combinatorial strategy for treating KRAS-mutant lung cancer. Nature, 534 (7609), 647–651 | 10.1038/nature18600 scihubto open science ↓ save