Single-cell DNA-seq depicts clonal evolution of multiple driver alterations in osimertinib-resistant patients

Chen, J.; Facchinetti, Fabio; Brayé, Floriane; Yurchenko, Andrey A.; Bigot, Ludovic; Ponce, Santiago; Planchard, David; Gazzah, Anas; Nikolaev, Sergey I.; Michiels, Stefan; Vasseur, Damien; Lacroix, Ludovic; Tsélikas, Lambros; Nobre, C.; Olaussen, Ken A.; André, Fabrice; Scoazec, Jean‐Yves; Soria, Jean‐Charles; Loriot, Yohann; Besse, Benjamin; Friboulet, Luc

doi:10.1016/j.annonc.2022.01.004

Cited by 17 publications

(16 citation statements)

References 29 publications

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“…Analysis of the single-cell DNA sequencing of the NSCLC cohort enrolled in the MATCH-R (NCT0251782) trial that developed osimertinib resistance revealed heterogeneity of acquired mutations in the cells including FGFR3-TACC3, KIF5B-RE , and STRN-ALK fusions that can be treated by existing drugs, thus suggesting possible treatments to overcome osimertinib resistance. 252 Similarly, RNA sequencing revealed that ALK junctional heterogeneity in NSCLC may predict resistance to crizotinib. 253 Likewise scRNA-seq of chemoresistant cervical cancer revealed induction of the (PI3K)/AKT pathway.…”

Section: Experimental Methods For Identification Of Fusion Oncogenesmentioning

confidence: 99%

Clinically relevant fusion oncogenes: detection and practical implications

et al. 2022

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Mechanistically, chimeric genes result from DNA rearrangements and include parts of preexisting normal genes combined at the genomic junction site. Some rearranged genes encode pathological proteins with altered molecular functions. Those which can aberrantly promote carcinogenesis are called fusion oncogenes. Their formation is not a rare event in human cancers, and many of them were documented in numerous study reports and in specific databases. They may have various molecular peculiarities like increased stability of an oncogenic part, self-activation of tyrosine kinase receptor moiety, and altered transcriptional regulation activities. Currently, tens of low molecular mass inhibitors are approved in cancers as the drugs targeting receptor tyrosine kinase (RTK) oncogenic fusion proteins, that is, including ALK, ABL, EGFR, FGFR1-3, NTRK1-3, MET, RET, ROS1 moieties. Therein, the presence of the respective RTK fusion in the cancer genome is the diagnostic biomarker for drug prescription. However, identification of such fusion oncogenes is challenging as the breakpoint may arise in multiple sites within the gene, and the exact fusion partner is generally unknown. There is no gold standard method for RTK fusion detection, and many alternative experimental techniques are employed nowadays to solve this issue. Among them, RNA-seq-based methods offer an advantage of unbiased high-throughput analysis of only transcribed RTK fusion genes, and of simultaneous finding both fusion partners in a single RNA-seq read. Here we focus on current knowledge of biology and clinical aspects of RTK fusion genes, related databases, and laboratory detection methods.

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Section: Experimental Methods For Identification Of Fusion Oncogenesmentioning

confidence: 99%

Clinically relevant fusion oncogenes: detection and practical implications

et al. 2022

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“…Tumors can show two or more resistance mechanisms, such as focal copy-number amplifications in MET, KRAS, and PD-L1, gene fusions of ALK, MKRN1-BRA, and ESR1-AKAP12, as well as neuroendocrine differentiation [153]. Therefore, combination therapy strategies have been strongly indicated in these cases [154].…”

Section: Clonal Evolution and Tumor Heterogeneity Within Mrdmentioning

confidence: 99%

Liquid Biopsy in Lung Cancer: Biomarkers for the Management of Recurrence and Metastasis

Souza

Forder²,

Brockley³

et al. 2023

IJMS

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Liquid biopsies have emerged as a promising tool for the detection of metastases as well as local and regional recurrence in lung cancer. Liquid biopsy tests involve analyzing a patient’s blood, urine, or other body fluids for the detection of biomarkers, including circulating tumor cells or tumor-derived DNA/RNA that have been shed into the bloodstream. Studies have shown that liquid biopsies can detect lung cancer metastases with high accuracy and sensitivity, even before they are visible on imaging scans. Such tests are valuable for early intervention and personalized treatment, aiming to improve patient outcomes. Liquid biopsies are also minimally invasive compared to traditional tissue biopsies, which require the removal of a sample of the tumor for further analysis. This makes liquid biopsies a more convenient and less risky option for patients, particularly those who are not good candidates for invasive procedures due to other medical conditions. While liquid biopsies for lung cancer metastases and relapse are still being developed and validated, they hold great promise for improving the detection and treatment of this deadly disease. Herein, we summarize available and novel approaches to liquid biopsy tests for lung cancer metastases and recurrence detection and describe their applications in clinical practice.

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“…[171][172][173] The combination of TKIs and inhibitors of downstream molecules or chemotherapeutic agents can effectively mitigate drug resistance. 174 Administration of multitargeted TKIs and combinations of different TKIs are more effective. For instance, cabozantinib is an oral multikinase inhibitor targeting VEGFR1/2/3, MET, and AXL and has an acceptable efficacy in patients with advanced HCC and GIST.…”

Section: Mechanisms Of Tki Resistancementioning

confidence: 99%

Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective

Yang

Wang

et al. 2022

Sig Transduct Target Ther

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Protein tyrosine kinases (PTKs) are a class of proteins with tyrosine kinase activity that phosphorylate tyrosine residues of critical molecules in signaling pathways. Their basal function is essential for maintaining normal cell growth and differentiation. However, aberrant activation of PTKs caused by various factors can deviate cell function from the expected trajectory to an abnormal growth state, leading to carcinogenesis. Inhibiting the aberrant PTK function could inhibit tumor growth. Therefore, tyrosine kinase inhibitors (TKIs), target-specific inhibitors of PTKs, have been used in treating malignant tumors and play a significant role in targeted therapy of cancer. Currently, drug resistance is the main reason for limiting TKIs efficacy of cancer. The increasing studies indicated that tumor microenvironment, cell death resistance, tumor metabolism, epigenetic modification and abnormal metabolism of TKIs were deeply involved in tumor development and TKI resistance, besides the abnormal activation of PTK-related signaling pathways involved in gene mutations. Accordingly, it is of great significance to study the underlying mechanisms of TKIs resistance and find solutions to reverse TKIs resistance for improving TKIs efficacy of cancer. Herein, we reviewed the drug resistance mechanisms of TKIs and the potential approaches to overcome TKI resistance, aiming to provide a theoretical basis for improving the efficacy of TKIs.

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Single-cell DNA-seq depicts clonal evolution of multiple driver alterations in osimertinib-resistant patients

Cited by 17 publications

References 29 publications

Clinically relevant fusion oncogenes: detection and practical implications

Clinically relevant fusion oncogenes: detection and practical implications

Liquid Biopsy in Lung Cancer: Biomarkers for the Management of Recurrence and Metastasis

Protein tyrosine kinase inhibitor resistance in malignant tumors: molecular mechanisms and future perspective

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