Targeting KRAS in Non-Small Cell Lung Cancer

Fuente, E. Corral de la; Garcia, Maria Eugenia Olmedo; Rueda, A. Gómez; Lage, Y.; Garrido, Pilar

doi:10.3389/fonc.2021.792635

Cited by 23 publications

(18 citation statements)

References 90 publications

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“…The half-life of adagrasib at 24.7 hours is also considerably longer than sotorasib, which is reported to be 5.5 hours. 30 , 31 In mouse models, sotorasib had an oral bioavailability of 22–40% compared to 62.9% with adagrasib. 32 Pre-clinical models also demonstrate different affinities for on-target resistance mutations between the two agents, as discussed below.…”

Section: Monotherapy With Sotorasib or Adagrasib In Kras ...mentioning

confidence: 99%

Targeting KRASG12C-Mutated Advanced Colorectal Cancer: Research and Clinical Developments

Ji¹,

Wang²,

Fakih³

2022

OTT

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Identifying mutations in the KRAS gene has become increasingly important in the treatment of colorectal cancer with many prognostic and therapeutic implications. However, efforts to develop drugs that target KRAS mutations have not been successful until more recently with the introduction of the KRAS G12C inhibitors, sotorasib (AMG510) and adagrasib (MRTX849). Both agents have demonstrated safety and promising efficacy in preclinical studies and early phase trials, but it appears that not all tumor types harboring the KRAS G12C mutation are sensitive to monotherapy approaches. In particular, patients with colorectal cancer (CRC) derive less benefit compared to those with non-small cell lung cancer (NSCLC), likely due to rapid treatment-induced resistance through increased epidermal growth factor receptor (EGFR) signaling. As a result, combination therapy trials with EGFR inhibitors are currently underway. Here, we will review the available clinical trial data on KRAS G12C inhibitors in KRAS G12C -mutated CRC, possible mechanisms of resistance to monotherapy, the research studying why available agents are proving to be less efficacious in CRC compared to NSCLC, and future directions for these promising new drugs.

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Section: Monotherapy With Sotorasib or Adagrasib In Kras ...mentioning

confidence: 99%

Targeting KRASG12C-Mutated Advanced Colorectal Cancer: Research and Clinical Developments

Ji¹,

Wang²,

Fakih³

2022

OTT

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“…Moreover, besides the different promising ICIs, new molecules are currently being evaluated in many clinical trials and recent results suggest the coming soon administration of additional targeted therapies for NS-NSCLC in daily practice [ 10 , 12 , 14 , 15 , 16 , 17 ]. Among these new drugs, some target KRAS mutations, particularly the KRAS G12C mutation [ 18 , 19 , 20 , 21 ]. The development of these therapies raises a lot of hope and expectations in thoracic oncology since the KRAS mutations, which have been considered for a long time as non-targetable, are identified in more than 30% of NSCLC patients, at least in Europe and in the US, depending on the different populations [ 15 , 22 , 23 , 24 , 25 , 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

Daily Practice Assessment of KRAS Status in NSCLC Patients: A New Challenge for the Thoracic Pathologist Is Right around the Corner

Bontoux

Hofman

Brest

et al. 2022

Cancers

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KRAS mutations are among the most frequent genomic alterations identified in non-squamous non-small cell lung carcinomas (NS-NSCLC), notably in lung adenocarcinomas. In most cases, these mutations are mutually exclusive, with different genomic alterations currently known to be sensitive to therapies targeting EGFR, ALK, BRAF, ROS1, and NTRK. Recently, several promising clinical trials targeting KRAS mutations, particularly for KRAS G12C-mutated NSCLC, have established new hope for better treatment of patients. In parallel, other studies have shown that NSCLC harboring co-mutations in KRAS and STK11 or KEAP1 have demonstrated primary resistance to immune checkpoint inhibitors. Thus, the assessment of the KRAS status in advanced-stage NS-NSCLC has become essential to setting up an optimal therapeutic strategy in these patients. This stimulated the development of new algorithms for the management of NSCLC samples in pathology laboratories and conditioned reorganization of optimal health care of lung cancer patients by the thoracic pathologists. This review addresses the recent data concerning the detection of KRAS mutations in NSCLC and focuses on the new challenges facing pathologists in daily practice for KRAS status assessment.

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“…Non–small cell lung cancer (NSCLC) is one of the leading causes of mortality in the world, and lung adenocarcinoma is identified as the most common pathological type of NSCLC ( Corral de la Fuente et al, 2021 ; Coleman et al, 2022 ). Though considerable manpower and research funds are applied to explore the mechanism of tumor formation and progression, the treatment efficiency for advanced lung adenocarcinoma is still unsatisfying.…”

Section: Introductionmentioning

confidence: 99%

CNTN-1 Upregulation Induced by Low-Dose Cisplatin Promotes Malignant Progression of Lung Adenocarcinoma Cells via Activation of Epithelial-Mesenchymal Transition

Zhang

Lan

et al. 2022

Front. Genet.

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Tumor metastasis and invasion are the main impediments to lung adenocarcinoma successful treatment. Previous studies demonstrate that chemotherapeutic agents can elevate the malignancy of cancer cells other than their therapeutic effects. In this study, the effects of transient low-dose cisplatin treatment on the malignant development of lung adenocarcinoma cells (A549) were detected, and the underlying epigenetic mechanisms were investigated. The findings showed that A549 cells exhibited epithelial-mesenchymal transition (EMT)-like phenotype along with malignant progression under the transient low-dose cisplatin treatment. Meanwhile, low-dose cisplatin was found to induce contactin-1 (CNTN-1) upregulation in A549 cells. Subsequently, we found that further overexpressing CNTN-1 in A549 cells obviously activated the EMT process in vitro and in vivo, and caused malignant development of A549 cells in vitro. Taken together, we conclude that low-dose cisplatin can activate the EMT process and resulting malignant progression through upregulating CNTN-1 in A549 cells. The findings provided new evidence that a low concentration of chemotherapeutic agents could facilitate the malignancy of carcinoma cells via activating the EMT process other than their therapeutic effects.

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Targeting KRAS in Non-Small Cell Lung Cancer

Cited by 23 publications

References 90 publications

Targeting KRASG12C-Mutated Advanced Colorectal Cancer: Research and Clinical Developments

Targeting KRASG12C-Mutated Advanced Colorectal Cancer: Research and Clinical Developments

Daily Practice Assessment of KRAS Status in NSCLC Patients: A New Challenge for the Thoracic Pathologist Is Right around the Corner

CNTN-1 Upregulation Induced by Low-Dose Cisplatin Promotes Malignant Progression of Lung Adenocarcinoma Cells via Activation of Epithelial-Mesenchymal Transition

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