Cellular Origins of EGFR‐Driven Lung Cancer Cells Determine Sensitivity to Therapy

Chen, Fan; Liu, Jinpeng; Flight, Robert M; Naughton, Kassandra J.; Lukyanchuk, Alexsandr; Edgin, Abigail R.; Song, Xiulong; Zhang, Haikuo; Wong, Kwok‐Kin; Moseley, Hunter N. B.; Wang, Chi; Brainson, Christine F.

doi:10.1002/advs.202101999

Cited by 19 publications

(17 citation statements)

References 55 publications

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“…While KRAS mutation is prevalent in smokers with chronic inflammation, EGFR mutation occurs preferentially in non-smokers. Consistent with the hypothesis that CC10 + cells require an inflammatory microenvironment to transform, Egfr mutant-driven lung cancer leads to an almost exclusively alveolar type LUAD, with a rare tumor exhibiting bronchiolar features [ 56 ]. Bronchiolar and alveolar tumor organoids have distinct drug responses highlighting the importance of cell of origin in cancer therapy response.…”

Section: Cell Of Origin Of Luad: Multiple Possibilitiessupporting

confidence: 59%

“…Bronchiolar and alveolar tumor organoids have distinct drug responses highlighting the importance of cell of origin in cancer therapy response. In addition, transcriptional analysis demonstrates that bronchiolar tumoroids have transcriptional enrichment in TNF- α , KRAS, mutated TP53, EGFR, BMI1 deletion and PRC2 activity associated pathways compared to alveolar tumoroids that express higher E2F targets and G2/M checkpoint genes, suggesting that oncogenic transformation drives distinct transcriptional landscapes in cells with different cellular origins [ 56 ].…”

Section: Cell Of Origin Of Luad: Multiple Possibilitiesmentioning

confidence: 99%

“…Retrospective analysis uncovered that immune checkpoint inhibitors (ICIs) responsiveness is influenced by tumor genetic alterations. While EGFR mutation leads to the inefficacy of ICIs, KRAS mutant tumors are the best responders [ 56 , 96 ]. However, the underlying association between KRAS mutation and immune responses remains unclear.…”

Section: Cell Of Origin Of Luad: the Interplay With The Immune Microe...mentioning

confidence: 99%

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Lung Adenocarcinoma Tumor Origin: A Guide for Personalized Medicine

Seguin

Durandy

Feral

2022

Cancers

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Lung adenocarcinoma, the major form of lung cancer, is the deadliest cancer worldwide, due to its late diagnosis and its high heterogeneity. Indeed, lung adenocarcinoma exhibits pronounced inter- and intra-tumor heterogeneity cofounding precision medicine. Tumor heterogeneity is a clinical challenge driving tumor progression and drug resistance. Several key pieces of evidence demonstrated that lung adenocarcinoma results from the transformation of progenitor cells that accumulate genetic abnormalities. Thus, a better understanding of the cell of origin of lung adenocarcinoma represents an opportunity to unveil new therapeutic alternatives and stratify patient tumors. While the lung is remarkably quiescent during homeostasis, it presents an extensive ability to respond to injury and regenerate lost or damaged cells. As the lung is constantly exposed to potential insult, its regenerative potential is assured by several stem and progenitor cells. These can be induced to proliferate in response to injury as well as differentiate into multiple cell types. A better understanding of how genetic alterations and perturbed microenvironments impact progenitor-mediated tumorigenesis and treatment response is of the utmost importance to develop new therapeutic opportunities.

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Section: Cell Of Origin Of Luad: Multiple Possibilitiessupporting

confidence: 59%

Section: Cell Of Origin Of Luad: Multiple Possibilitiesmentioning

confidence: 99%

Section: Cell Of Origin Of Luad: the Interplay With The Immune Microe...mentioning

confidence: 99%

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Lung Adenocarcinoma Tumor Origin: A Guide for Personalized Medicine

Seguin

Durandy

Feral

2022

Cancers

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“…For each mutant, they were also grown in different ways and sequenced: (1) 2D plates; (2) 3D organoids; (3) cells sorted and selected using FACS; (4) total tumor without sorting. See [25] for the full experimental details.…”

Section: Brainson Rna-seq Data Setmentioning

confidence: 99%

Information-Content-Informed Kendall-tau Correlation: Utilizing Missing Values

Flight

Bhatt

Moseley

2022

Preprint

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Almost all correlation measures currently available are unable to handle missing values. Typically, missing values are either ignored completely by removing them or are imputed and used in the calculation of the correlation coefficient. In both cases, the correlation value will be impacted based on a perspective that missing data represents no useful information. However, missing values occur in real data sets for a variety of reasons. In omics data sets that are derived from analytical measurements, the primary reason for missing values is that a specific measurable phenomenon falls below the detection limits of the analytical instrumentation. These missing data are not missing at random, but represent some information by their "missingness." Therefore, we propose an information-content-informed Kendall-tau (ICI-Kt) correlation coefficient that allows missing values to carry explicit information in the determination of concordant and discordant pairs. With both simulated and real data sets from RNA-seq experiments, we demonstrate that the ICI-Kt allows for the inclusion of missing data values as interpretable information. Moreover, our implementation of ICI-Kt uses a mergesort-like algorithm that provides O(nlog(n)) computational performance. Finally, we show that approximate ICI-Kt correlations can be calculated using smaller feature subsets of large data sets with significant time savings, which has practical computational value when feature sizes are very large. The ICI-Kt correlation calculation is available in an R package and Python module on GitHub at https://github.com/moseleyBionformaticsLab/ICIKendallTau and https://github.com/moseleyBionformaticsLab/icikt, respectively.

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“…Mutations within the epidermal growth factor receptor ( EGFR ) are an important driver of lung cancers. Targeting EGFR with tyrosine kinase inhibitors (TKIs) is the main precision medicine treatment option and the standard treatment for lung adenocarcinoma (LADC) patients harboring EGFR activating mutations ( 1 , 2 ). EGFR -TKIs have markedly improved the prognoses of patients with non-small cell lung cancer (NSCLC) harboring EGFR -activating mutations.…”

Section: Introductionmentioning

confidence: 99%

Case Report: Durable partial response to icotinib plus crizotinib in a lung adenocarcinoma patient with double uncommon EGFR G719D/L861Q mutations and an acquired novel CUX1-MET fusion

Tang

Deng

et al. 2022

Front. Oncol.

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Non-small cell lung cancer (NSCLC) patients harboring MET exon 14 skipping or high MET amplification display a high rate of response to MET inhibitors. However, MET fusions in NSCLC have rarely been revealed. In this report, a 63-year-old woman with lung adenocarcinoma (LADC), harboring EGFR exon 18 G719D and exon 21 L861Q mutations, received first-generation, EGFR-tyrosine kinase inhibitor (TKI) icotinib therapy. Next generation sequencing (NGS) results only displayed an EGFR T790M point mutation following icotinib resistance. Thus, the patient was treated with osimertinib and achieved a stable disease (SD). However, disease progressed after 15 months and a novel MET fusion (CUX1 exon14-MET exon15) in addition to EGFR G719D/L861Q mutations were simultaneously detected in a tissue biopsy sample. After more than nine months, the patient subsequently achieved a PR with the combination of icotinib and crizotinib. To our knowledge, this is the first case of LADC patient displaying the presence of EGFR double uncommon mutations and an acquired novel CUX1-MET fusion that has benefited from icotinib plus crizotinib treatment. Following nine months of PR with icotinib plus crizotinib, the patient, until the time of publication, is exhibiting stable disease. The results suggest that the CUX1-MET fusion may be sensitive to crizotinib, although previous reports indicated that some MET fusion cases did not respond to crizotinib. Given this disparity, distinguishing MET fusion partners when crizotinib is used in LADC treatment is also very important.

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Cellular Origins of EGFR‐Driven Lung Cancer Cells Determine Sensitivity to Therapy

Cited by 19 publications

References 55 publications

Lung Adenocarcinoma Tumor Origin: A Guide for Personalized Medicine

Lung Adenocarcinoma Tumor Origin: A Guide for Personalized Medicine

Information-Content-Informed Kendall-tau Correlation: Utilizing Missing Values

Case Report: Durable partial response to icotinib plus crizotinib in a lung adenocarcinoma patient with double uncommon EGFR G719D/L861Q mutations and an acquired novel CUX1-MET fusion

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