Two Cases of Small Cell Lung Cancer Transformation from EGFR Mutant Adenocarcinoma During AZD9291 Treatment

Ham, Jun Soo; Kim, Seokhwi; Kim, Hee Kyung; Byeon, Seonggyu; Sun, Jong‐Mu; Lee, Sehoon; Ahn, Jin Seok; Park, Keunchil; Choi, Yoon‐La; Han, Joungho; Park, Woong-Yang; Ahn, Myung‐Ju

doi:10.1016/j.jtho.2015.09.013

Cited by 71 publications

(54 citation statements)

References 6 publications

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“…In the article elucidating mechanisms of acquired resistance to AZD9291 by Kim et al in 2015, one patient was found as SCLC transformation [8]. And another two cases of small cell carcinoma transformation were also reported during AZD9291 treatment in 2016 [9]. Here we also reported a case of SCLC transformation after 6 months of AZD9291 treatment.…”

Section: Discussionsupporting

confidence: 61%

Transformation to small-cell carcinoma as an acquired resistance mechanism to AZD9291: A case report

Wang

et al. 2017

Oncotarget

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AZD9291, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), benefits patients with T790M mutant non-small-cell lung cancer who fail treatment with first-generation EGFR TKIs. Acquisition of resistance to AZD9291 occurs inevitable and mechanisms need to be explored. We reported an advanced lung adenocarcinoma female with EGFR exon19 deletion treated on AZD9291 after failure of erlotinib and chemotherapy. Disease progressed again after 6 months treatment of AZD9291 with hepatic metastasis. Re-biopsy of the hepatic lesion showed histopathology transformation to small cell lung cancer, which harbored EGFR exon19 deletion. Therefore, small cell carcinoma transformation is one of potential resistance mechanisms to AZD9291 and regimen for small cell carcinoma may be one of the treatment options.

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Section: Discussionsupporting

confidence: 61%

Transformation to small-cell carcinoma as an acquired resistance mechanism to AZD9291: A case report

Wang

et al. 2017

Oncotarget

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“…Consistent with previous reports referred to acquired resistance to first-generation of TKI (20), the transformed SCLCs continued to harbor their original EGFR-activating mutations, but not T790M; one patient developed a mutation in RB1 and the other lost expression of RB1, evaluated by immunohistochemistry. Kim et al and Ham et al published the same mechanism of acquired resistance for osimertinib separately (28,29 …”

Section: Sclc Transformationmentioning

confidence: 97%

Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in T790M-positive non-small cell lung cancer: review on emerged mechanisms of resistance

Minari

Bordi

Tiseo

2016

Transl. Lung Cancer Res.

160

161

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“…Recently, osimertinib, a third‐generation EGFR‐TKI, was developed to overcome the resistance associated with the EGFR T790M mutation, and is expected to play an important role in the treatment of advanced NSCLC . However, the emergence of resistance to osimertinib by various mechanisms, including the appearance of the EGFR C797S mutation, has already become a serious problem . These phenomena demand the development of novel therapeutic strategies for advanced NSCLC with acquired resistance to EGFR‐TKIs.…”

Section: Introductionmentioning

confidence: 99%

Combined inhibition of MEK and PI3K pathways overcomes acquired resistance to EGFR‐TKIs in non‐small cell lung cancer

et al. 2018

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Compensatory activation of the signal transduction pathways is one of the major obstacles for the targeted therapy of non‐small cell lung cancer (NSCLC). Herein, we present the therapeutic strategy of combined targeted therapy against the MEK and phosphoinositide‐3 kinase (PI3K) pathways for acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in NSCLC. We investigated the efficacy of combined trametinib plus taselisib therapy using experimentally established EGFR‐TKI‐resistant NSCLC cell lines. The results showed that the feedback loop between MEK/ERK and PI3K/AKT pathways had developed in several resistant cell lines, which caused the resistance to single‐agent treatment with either inhibitor alone. Meanwhile, the combined therapy successfully regulated the compensatory activation of the key intracellular signals and synergistically inhibited the cell growth of those cells in vitro and in vivo. The resistance mechanisms for which the dual kinase inhibitor therapy proved effective included (MET) mesenchymal‐epithelial transition factor amplification, induction of epithelial‐to‐mesenchymal transition (EMT) and EGFR T790M mutation. In further analysis, the combination therapy induced the phosphorylation of p38 MAPK signaling, leading to the activation of apoptosis cascade. Additionally, long‐term treatment with the combination therapy induced the conversion from EMT to mesenchymal‐to‐epithelial transition in the resistant cell line harboring EMT features, restoring the sensitivity to EGFR‐TKI. In conclusion, our results indicate that the combined therapy using MEK and PI3K inhibitors is a potent therapeutic strategy for NSCLC with the acquired resistance to EGFR‐TKIs.

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Two Cases of Small Cell Lung Cancer Transformation from EGFR Mutant Adenocarcinoma During AZD9291 Treatment

Cited by 71 publications

References 6 publications

Transformation to small-cell carcinoma as an acquired resistance mechanism to AZD9291: A case report

Transformation to small-cell carcinoma as an acquired resistance mechanism to AZD9291: A case report

Third-generation epidermal growth factor receptor-tyrosine kinase inhibitors in T790M-positive non-small cell lung cancer: review on emerged mechanisms of resistance

Combined inhibition of MEK and PI3K pathways overcomes acquired resistance to EGFR‐TKIs in non‐small cell lung cancer

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