An Acquired NRAS Q61K Mutation in BRAF V600E-Mutant Lung Adenocarcinoma Resistant to Dabrafenib Plus Trametinib

Abravanel, Daniel L.; Nishino, Mizuki; Sholl, Lynette M.; Ambrogio, Chiara; Awad, Mark M.

doi:10.1016/j.jtho.2018.03.026

Cited by 29 publications

(10 citation statements)

References 14 publications

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“…C797S mutation is known to contribute to osimertinib resistance in the Japanese population [24]. Other possible resistance‐related genotypes such as BRAF V600E [25] and NRAS Q61K [25,26] in ctDNA were also detected by NGS at PD/stop in this study. These mutations are actionable for activation of bypass pathways such as BRAF and MAPK signaling pathways.…”

Section: Discussionmentioning

confidence: 70%

Predicting osimertinib‐treatment outcomes through EGFR mutant‐fraction monitoring in the circulating tumor DNA of EGFR T790M‐positive patients with non‐small cell lung cancer (WJOG8815L)

et al. 2020

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In the WJOG8815L phase II clinical study, we monitored EGFR mutation fractions (MFs) in the circulating tumor DNA (ctDNA) of EGFR T790M mutation‐positive patients with non‐small cell lung cancer (NSCLC) that received treatment with the tyrosine kinase inhibitor (TKI) osimertinib. The MF values of TKI‐sensitizing EGFR mutations in ctDNA at day 1 of cycle 4 of osimertinib treatment could predict osimertinib treatment outcomes.

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Section: Discussionmentioning

confidence: 70%

Predicting osimertinib‐treatment outcomes through EGFR mutant‐fraction monitoring in the circulating tumor DNA of EGFR T790M‐positive patients with non‐small cell lung cancer (WJOG8815L)

et al. 2020

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“…In addition, KRAS and NRAS mutations on codons 12 and 61 have been identified both in preclinical models of resistance to MKIs in RET-altered cells [123] and in MET-, NTRK-, and BRAF-altered patients after progressing to frontline targeted therapies [126,[128][129][130][131][132]. Similarly, MEK1 activating mutations were described in case reports of BRAF V600E NSCLC after progression to dabrafenib and trametinib [133] as well as in NTRK-rearranged patients after TKI treatment [126].…”

Section: Signaling Bypass Activation and Other Resistance Mechanismsmentioning

confidence: 97%

Targeting Infrequent Driver Alterations in Non-Small Cell Lung Cancer

et al. 2021

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The discovery of oncogenic driver mutations led to the development of targeted therapies with non-small cell lung cancer (NSCLC) being a paradigm for precision medicine in this setting. Nowadays, the number of clinical trials focusing on targeted therapies for uncommon drivers is growing exponentially, emphasizing the medical need for these patients. Unfortunately, similar to what is observed with most targeted therapies directed against a driver oncogene, the clinical response is almost always temporary and acquired resistance to these drugs invariably emerges. Here, we review the biology of infrequent genomic actionable alterations in NSCLC as well as the current and emerging therapeutic options for these patients. Mechanisms leading to acquired drug resistance and future challenges in the field are also discussed. The Challenge of Targeted Therapy in NSCLC Driven by Uncommon Genetic AlterationsThe expanding spectrum of oncogenic driver mutations and clinically available signaling pathway inhibitors had a major impact on non-small cell lung cancer (NSCLC) (see Glossary) patient management in the past decade [1]. Cancer driver mutations not only initiate the disease but also sustain tumor progression and therefore their inhibition results in a therapeutic benefit. Driver oncogenes are often identified due to their recurrence in patients, a complicated feature when they appear with low prevalence, as those covered in this review. Yet the oncogenic nature and the addiction of cancer cells to this set of infrequent drivers have been clearly established, as well as their mutually exclusive pattern with other oncogenes. With the exception of BRAF, all belong to the receptor tyrosine kinase (RTK) family and, when in the oncogenic form, constantly activate essential downstream signaling pathways, including MAPK, PI3K, and JNK, resulting in sustained growth, increased survival, and enhanced dissemination. Recently, the FDA has approved specific inhibitors targeting infrequent NSCLC oncogenic drivers (ROS1, MET, RET, BRAF, and NTRK). Beyond those, promising preliminary data with compounds targeting other emerging driver alterations (e.g., HER2) have been reported [2]. Used as first or latter lines of treatment (after standard chemotherapy and/or immunotherapy), these targeted therapies have greatly increased patient outcome [3][4][5][6][7][8][9]. Unfortunately, as anticipated by the lessons learned from the clinical management of EGFR-mutated and ALK-rearranged lung adenocarcinoma (LUAD) (Box 1), therapeutic resistance eventually appears in most patients and, therefore, advanced NSCLC remains largely incurable (for review see [10]). In the present review, we describe the biological relevance and the therapeutic options of a series of infrequent drivers for which clinical treatments have been approved or are under evaluation. Likewise, the clinical management of on-target resistance is discussed per driver, while that due to bypass signaling is collectively addressed given its pan-driver conservation. ROS1Biological and C...

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“…Cyclin-dependent kinase 4 upregulation mediates acquired resistance of dabrafenib plus trametinib in BRAF V600E-mutated lung cancer 3-kinase (PI3K)/AKT pathways have been reported, the mechanisms of resistance to DT therapy are unclear (2)(3)(4).…”

Section: Original Articlementioning

confidence: 99%

Cyclin-dependent kinase 4 upregulation mediates acquired resistance of dabrafenib plus trametinib in BRAF V600E-mutated lung cancer

Hirai¹,

Hatanaka²,

Hatanaka³

et al. 2021

Transl Lung Cancer Res

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Background: Combination therapy with the B-Raf inhibitor, dabrafenib, and the MEK inhibitor, trametinib (DT) is commonly used to treat patients with B-Raf proto-oncogene, serine/threonine kinase V600E (BRAF V600E)-mutated non-small cell lung cancer (NSCLC). However, the mechanisms through which cancer develops DT resistance are unclear. Here, we investigated new mechanisms underlying acquired DT-resistant NSCLC with the BRAF V600E mutation.Methods: We compared genomic signatures before and after DT treatment in patients with NSCLC.Results: Two of four patients treated with DT developed carcinomatous pleuritis within 3 months.Target DNA sequencing and quantitative polymerase chain reaction (PCR) analyses revealed the increased expression level of cyclin-dependent kinase 4 (CDK4). We also found prominent protein expression of CDK4 after DT treatment. Induction of CDK4 expression in a cell line derived from a patient with the BRAF V600E mutation resulted in partial resistance to dabrafenib.Conclusions: Our findings suggest a possible relationship between CDK4 upregulation and acquired resistance to DT therapy.

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An Acquired NRAS Q61K Mutation in BRAF V600E-Mutant Lung Adenocarcinoma Resistant to Dabrafenib Plus Trametinib

Cited by 29 publications

References 14 publications

Predicting osimertinib‐treatment outcomes through EGFR mutant‐fraction monitoring in the circulating tumor DNA of EGFR T790M‐positive patients with non‐small cell lung cancer (WJOG8815L)

Predicting osimertinib‐treatment outcomes through EGFR mutant‐fraction monitoring in the circulating tumor DNA of EGFR T790M‐positive patients with non‐small cell lung cancer (WJOG8815L)

Targeting Infrequent Driver Alterations in Non-Small Cell Lung Cancer

Cyclin-dependent kinase 4 upregulation mediates acquired resistance of dabrafenib plus trametinib in BRAF V600E-mutated lung cancer

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