profiling-sensitivity-to-targeted-therapies-egfr-mutant-nsclc-patient

Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids

Novel 3D cancer organoid cultures derived from clinical patient specimens represent an important model system to evaluate intratumor heterogeneity and ...

University of California, San Francisco

Pathologic Complete Response to Neoadjuvant Crizotinib in a Lung Adenocarcinoma Patient With a MET Exon 14 Skipping Mutation.

Although patients with advanced-stage non-small cell lung cancers (NSCLC) harboring  exon 14 skipping mutations (ex14) often benefit from MET tyrosine kinase inhibitor (TKI) treatment, clinical benefit is limited by primary and acquired drug resistance. The molecular basis for this resistance remains incompletely understood.

Co-occurring Alterations in the RAS-MAPK Pathway Limit Response to MET Inhibitor Treatment in MET Exon 14 Skipping Mutation-Positive Lung Cancer.

The clinical utility of performing tumor genetic testing to assess for alterations beyond the known targetable oncogenes in lung adenocarcinoma is unclear. Analyzing cancer pathway alterations beyond single oncogenic driver mutations in addition to markers of tumor mutation burden and genomic instability may provide additional predictive and prognostic information..

A New Pathway Emerges to Interpret Lung Cancer Genomic Alterations.

Lung cancer, the leading cause of cancer mortality, exhibits heterogeneity that enables adaptability, limits therapeutic success, and remains incompletely understood. Single-cell RNA sequencing (scRNA-seq) of metastatic lung cancer was performed using 49 clinical biopsies obtained from 30 patients before and during targeted therapy. Over 20,000 cancer and tumor microenvironment (TME) single-cell profiles exposed a rich and dynamic tumor ecosystem. scRNA-seq of cancer cells illuminated targetable oncogenes beyond those detected clinically. Cancer cells surviving therapy as residual disease (RD) expressed an alveolar-regenerative cell signature suggesting a therapy-induced primitive cell-state transition, whereas those present at on-therapy progressive disease (PD) upregulated kynurenine, plasminogen, and gap-junction pathways. Active T-lymphocytes and decreased macrophages were present at RD and immunosuppressive cell states characterized PD. Biological features revealed by scRNA-seq were biomarkers of clinical outcomes in independent cohorts. This study highlights how therapy-induced adaptation of the multi-cellular ecosystem of metastatic cancer shapes clinical outcomes.

Article	Year
Pathologic Complete Response to Neoadjuvant Crizotinib in a Lung Adenocarcinoma Patient With a MET Exon 14 Skipping Mutation. Clinical lung cancer\| PubMed ID: 30553716	2019
Co-occurring Alterations in the RAS-MAPK Pathway Limit Response to MET Inhibitor Treatment in MET Exon 14 Skipping Mutation-Positive Lung Cancer. Clinical cancer research : an official journal of the American Association for Cancer Research\| PubMed ID: 31548343	2020
A New Pathway Emerges to Interpret Lung Cancer Genomic Alterations. Clinical cancer research : an official journal of the American Association for Cancer Research\| PubMed ID: 31611281	2019
Therapy-Induced Evolution of Human Lung Cancer Revealed by Single-Cell RNA Sequencing. Cell\| PubMed ID: 32822576	2020

Collin M. Blakely

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