Comparison of clinical outcome after first-line platinum-based chemotherapy in different types of KRAS mutated advanced non-small-cell lung cancer

Mellema, Wouter W.; Masen-Poos, Lucie; Smit, Egbert F.; Hendriks, Lizza; Aerts, Joachim; Termeer, A.; Goosens, Martijn; Smit, Hans; Heuvel, Michel M. van den; Wekken, Anthonie J. van der; Herder, Gerarda J.M.; Krouwels, Frans H.; Stigt, Jos A.; Borne, Ben E. E. M. van den; Haitjema, T.; Brekel, A.J. Staal-van den; Heemst, Robbert C. van; Pouw, E.M.; Dingemans, Anne‐Marie C.

doi:10.1016/j.lungcan.2015.09.012

Cited by 34 publications

(38 citation statements)

References 23 publications

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“…In vitro analysis of cell lines carrying various KRAS mutants showed that replacement of a single amino acid results in distinct phosphorylation patterns and leads to different signal transduction cascades (7). Of the 14 KRAS mutation types that we detected in our study population, mutations in exon 2 codon G12 were found most frequently, in agreement with other cohorts (14,16,17). The most common variants were G12C and G12V that occurred with a combined frequency of 60%.…”

Section: Discussionsupporting

confidence: 92%

“…While standard platinum based doublet chemotherapy remains the recommended treatment option in a large group of patients with mutated KRAS, studies are emerging highlighting different sensitivity patterns in distinct KRAS variants (14,16,17). In particular, Garassino et al found significant differences in treatment response to cisplatin among KRAS overexpressing clones of human lung adenocarcinoma cells with G12V mutant cells responding better to cisplatin chemotherapy and G12C showing the least response (18).…”

Section: Discussionmentioning

confidence: 99%

“…In particular, Garassino et al found significant differences in treatment response to cisplatin among KRAS overexpressing clones of human lung adenocarcinoma cells with G12V mutant cells responding better to cisplatin chemotherapy and G12C showing the least response (18). In a study by Mellema et al patients with G12V had better response to taxane treatment (16). Therefore the simple definition of KRAS-mutated tumor is no longer enough to identify patients with a different response profile to chemotherapeutics.…”

Section: Discussionmentioning

confidence: 99%

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The potential utility of re-mining results of somatic mutation testing: KRAS status in lung adenocarcinoma

et al. 2016

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KRAS mutant non-small cell lung cancers (NSCLCs) vary in clinical outcome depending on which specific KRAS mutation is present. Shorter progression free survival has been associated with KRAS variants G12C and G12V. Cell lines with these variants depend to a greater extent on the RAS/RAF/MEK/ERK signaling pathway and become more susceptible to MEK inhibition. Because different KRAS mutations may lead to altered drug sensitivity, we aimed to determine specific KRAS mutation status in a NSCLC patient cohort at our institution. A total of 502 NSCLC samples were screened for somatic mutations using the 50 gene AmpliSeq™ Cancer Hotspot Panel v2 (CHPv2). However only samples positive for variants in the KRAS gene were included in this study. Variants identified in the KRAS genes were curated using publicly available databases. The overall mutation rate in the KRAS gene was 32.7% (164/502). The most common KRAS mutations were G12C (41%), G12V (19%), and G12D (14%) along with less frequent variants. After re-mining our sequencing data, we found that more than a half of our KRAS mutant NSCLC patients could potentially benefit from the addition of a MEK inhibitor such as selumetinib to standard chemotherapeutic agents. Due to mutated KRAS, these patients will likely fail traditional anti-EGFR therapies but be eligible for newer combination therapies.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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The potential utility of re-mining results of somatic mutation testing: KRAS status in lung adenocarcinoma

et al. 2016

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“…Mellema et al investigated platinum first line association with a second agent (pemetrexed, taxane, gemcitabine, bevacizumab plus taxane) in KRAS-mutated patients. It was proven that NSCLC KRAS-mutated patients had better ORR if treated with taxane [ 106 ].…”

Section: Mutations or Translocations Other Than Egfr/alkmentioning

confidence: 99%

Targeted therapies and immunotherapy in non-small-cell lung cancer

Cortinovis¹,

Abbate²,

Bidoli³

et al. 2016

ecancer

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Non-small-cell lung cancer is still considered a difficult disease to manage because of its aggressiveness and resistance to common therapies. Chemotherapy remains the gold standard in nearly 80% of lung cancers, but clinical outcomes are discouraging, and the impact on median overall survival (OS) barely reaches 12 months.At the end of the last century, the discovery of oncogene-driven tumours completely changed the therapeutic landscape in lung cancers, harbouring specific gene mutations/translocations. Epidermal growth factors receptor (EGFR) common mutations first and anaplastic lymphoma kinase (ALK) translocations later led new insights in lung cancer biology knowledge. The use of specific tyrosine kinases inhibitors overturned the biological behaviour of EGFR mutation positive tumours and became a preclinical model to understand the heterogeneity of lung cancers and the mechanisms of drug resistance. In this review, we summarise the employment of targeted agents against the most representative biomolecular alterations and provide some criticisms of the therapeutic strategies.

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“…In addition, the lung cancer patients with KRAS G12V exhibited worse overall survival (OS) and higher recurrence incidences [15,16]. The lung cancer patients with different KRAS mutations display distinct sensitivity to chemotherapy and targeted therapy [17][18][19]. In the Biomarker-integrated Approaches of Targeted Therapy for Lung Cancer Elimination (BATTLE) trial, Ihle, N.T.…”

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confidence: 99%

The Inhibition of Wnt Restrain KRASG12V-Driven Metastasis in Non-Small-Cell Lung Cancer

Hung

Huang

Kuo

et al. 2020

Cancers

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The KRAS mutations have been an obstacle to identify therapeutic targets in cancer treatment. In this work, we clarified the distinct metastasis pattern of non-small-cell lung carcinoma (NSCLC) induced by KRASG12V/KRASG12D mutations and inhibited the KRASG12V mediated metastasis by Wnt inhibitor. First, we found that KRASG12V induced more aggressive phenotype in vitro and in vivo experiments. The Gene Set Enrichment Analysis (GSEA) results of H838 KRASG12V cells showed a significant negative correlation with RhoA-related signaling. Following this clue, we observed KRASG12D induced higher activation of RhoA and suppressed activation of Wnt/β-catenin in H838KRASG12D cells. The restored activation of Wnt/β-catenin in H838KRASG12D cells could be detected when expression with a dominant-negative mutant of RhoA or treatment with RhoA inhibitor. Furthermore, the Wnt inhibitor abolished the KRASG12V-induced migration. We elucidated the importance of the axis of RhoA/Wnt in regulatory NSCLC metastasis driven by KRAS mutations. Our data indicate that KRASG12V driven NSCLC metastasis is Wnt-dependent and the mechanisms of NSCLC metastasis induced by KRASG12V/KRASG12D is distinct.

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Comparison of clinical outcome after first-line platinum-based chemotherapy in different types of KRAS mutated advanced non-small-cell lung cancer

Abstract: KRAS mutated NSCLC patients treated with taxane-based chemotherapy had best ORR. Response to chemotherapy regimens was different in types of KRAS mutation. Especially patients with G12V had better response to taxane treatment.

Cited by 34 publications

References 23 publications

The potential utility of re-mining results of somatic mutation testing: KRAS status in lung adenocarcinoma

The potential utility of re-mining results of somatic mutation testing: KRAS status in lung adenocarcinoma

Targeted therapies and immunotherapy in non-small-cell lung cancer

The Inhibition of Wnt Restrain KRASG12V-Driven Metastasis in Non-Small-Cell Lung Cancer

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