Genetic Mutation Screen in Early Non–Small-Cell Lung Cancer (NSCLC) Specimens

Bar, Jair; Damianovich, Maya; Siloni, Goni Hout; Dar, Erel; Cohen, Yoram; Perelman, Marina; Nun, Alon Ben; Simansky, David; Yellin, Alon; Urban, Damien; Onn, Amir

doi:10.1016/j.cllc.2013.11.005

Cited by 13 publications

(10 citation statements)

References 31 publications

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“…Oncogenic KRAS mutations occur in approximately 30% of all cancer types and in 20–30% of non-small cell lung cancers (NSCLC) (3). These oncogenic mutations frequently occur as point mutations in codons 12, 13, or 61, each resulting in a protein with impaired GTPase activity, and therefore, constitutive activation of RAS signaling (3,4). A large body of literature has reported that cancers with oncogenic KRAS mutations are resistant to anti-cancer drug treatments and thus patients with these malignancies have poor prognoses (5–9).…”

Section: Introductionmentioning

confidence: 99%

Oncogenic KRAS Confers Chemoresistance by Upregulating NRF2

et al. 2014

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Oncogenic KRAS mutations found in 20–30% of all non-small cell lung cancers (NSCLC) are associated with chemoresistance and poor prognosis. Here we demonstrate that activation of the cell protective stress response gene NRF2 by KRAS is responsible for its ability to promote drug resistance. RNAi-mediated silencing of NRF2 was sufficient to reverse resistance to cisplatin elicited by ectopic expression of oncogenic KRAS in NSCLC cells. Mechanistically, KRAS increased NRF2 gene transcription through a TPA response element (TRE) located in the NRF2 promoter. In a mouse model of mutant KrasG12D-induced lung cancer, we found that suppressing the NRF2 pathway with the chemical inhibitor brusatol enhanced the antitumor efficacy of cisplatin. Co-treatment reduced tumor burden and improved survival. Our findings illuminate the mechanistic details of KRAS-mediated drug resistance and provide a preclinical rationale to improve the management of lung tumors harboring KRAS mutations with NRF2 pathway inhibitors.

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Section: Introductionmentioning

confidence: 99%

Oncogenic KRAS Confers Chemoresistance by Upregulating NRF2

et al. 2014

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“…Oberholzer et al showed that RAS mutations by MALDI-TOF MS are more frequent in cutaneous squamous cell tumor patients treated with RAF inhibitors than in those not so treated. 21 Bar et al 22 also demonstrated the Sequenom-based mutation screen is feasible using FFPE samples in NSCLC. In the same way, Su et al detected EGFRT790M mutations in patients with non-small-cell lung cancer, which detected and quantified the mutations highly sensitively.…”

Section: Discussionmentioning

confidence: 99%

“…Additional studies on multigene profiling have demonstrated the coexistence of mutations in multiple genes, which suggests that those driver mutations may lie molecularly upstream or downstream of one another or may predict different efficacies of targeted therapy. 12 – 14 Some studies reported that ALK and EGFR can be co-mutated. 15 , 16 One study included a patient with 5 different genetic alterations.…”

Section: Introductionmentioning

confidence: 99%

Concurrent Oncogene Mutation Profile in Chinese Patients With Stage Ib Lung Adenocarcinoma

et al. 2014

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“…This type of testing could significantly affect both early treatment decisions and those for patients with advanced or metastatic disease. Indeed, multiplex hot spot analyses, for example with Sequenom ® MassARRAY platform mutation screening, is feasible on FFPE specimens and has been shown to detect genetic abnormalities in early NSCLC [62]. Multiplexed deep sequencing analysis of ALK kinase domain has also identified resistance mutations in relapsed patients following crizotinib treatment [63].…”

Section: Current Pathologic and Molecular Testing Guidelinesmentioning

confidence: 98%

Diagnostic Challenges in Non-Small-Cell Lung Cancer: An Integrated Medicine Approach

Salgia¹

2015

Future Oncol.

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The discovery of diverse driver mutations in lung cancer has heralded a new era of personalized medicine in thoracic oncology, with targeted therapies approved for specific subgroups of patients. The increasing number of patient subgroups that may respond to targeted therapy has resulted in a greater reliance upon effective and increasingly complex diagnostics, which must be interpreted in an interactive multidisciplinary forum. This review discusses the molecular diagnostics available and under development for established and emerging targets, and how these may be integrated into current treatment algorithms. The roles of the pulmonologist, interventional radiologist, thoracic surgeon and molecular pathologist are discussed, and their interactions with the medical oncologist, and/or thoracic surgeon and radiation oncologist in making individual treatment decisions.

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Genetic Mutation Screen in Early Non–Small-Cell Lung Cancer (NSCLC) Specimens

Cited by 13 publications

References 31 publications

Oncogenic KRAS Confers Chemoresistance by Upregulating NRF2

Oncogenic KRAS Confers Chemoresistance by Upregulating NRF2

Concurrent Oncogene Mutation Profile in Chinese Patients With Stage Ib Lung Adenocarcinoma

Diagnostic Challenges in Non-Small-Cell Lung Cancer: An Integrated Medicine Approach

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