We are analyzing https://link.springer.com/article/10.1186/s13045-019-0818-2.

Title:
Emerging insights of tumor heterogeneity and drug resistance mechanisms in lung cancer targeted therapy | Journal of Hematology & Oncology
Description:
The biggest hurdle to targeted cancer therapy is the inevitable emergence of drug resistance. Tumor cells employ different mechanisms to resist the targeting agent. Most commonly in EGFR-mutant non-small cell lung cancer, secondary resistance mutations on the target kinase domain emerge to diminish the binding affinity of first- and second-generation inhibitors. Other alternative resistance mechanisms include activating complementary bypass pathways and phenotypic transformation. Sequential monotherapies promise to temporarily address the problem of acquired drug resistance, but evidently are limited by the tumor cells’ ability to adapt and evolve new resistance mechanisms to persist in the drug environment. Recent studies have nominated a model of drug resistance and tumor progression under targeted therapy as a result of a small subpopulation of cells being able to endure the drug (minimal residual disease cells) and eventually develop further mutations that allow them to regrow and become the dominant population in the therapy-resistant tumor. This subpopulation of cells appears to have developed through a subclonal event, resulting in driver mutations different from the driver mutation that is tumor-initiating in the most common ancestor. As such, an understanding of intratumoral heterogeneity—the driving force behind minimal residual disease—is vital for the identification of resistance drivers that results from branching evolution. Currently available methods allow for a more comprehensive and holistic analysis of tumor heterogeneity in that issues associated with spatial and temporal heterogeneity can now be properly addressed. This review provides some background regarding intratumoral heterogeneity and how it leads to incomplete molecular response to targeted therapies, and proposes the use of single-cell methods, sequential liquid biopsy, and multiregion sequencing to discover the link between intratumoral heterogeneity and early adaptive drug resistance. In summary, minimal residual disease as a result of intratumoral heterogeneity is the earliest form of acquired drug resistance. Emerging technologies such as liquid biopsy and single-cell methods allow for studying targetable drivers of minimal residual disease and contribute to preemptive combinatorial targeting of both drivers of the tumor and its minimal residual disease cells.
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Keywords {🔍}

pubmed, cancer, resistance, article, google, scholar, tumor, cas, cells, drug, lung, egfr, central, therapy, cell, response, treatment, patients, acquired, heterogeneity, targeted, mutations, mutation, nsclc, tumors, molecular, oncol, disease, early, residual, kinase, inhibitors, clinical, signaling, evolution, phase, mechanisms, met, inhibition, clin, med, adaptive, osimertinib, emergence, advanced, nonsmall, res, egfrmutant, minimal, therapeutic,

Topics {✒️}

related subjects raf-mek-erk signaling cascade nf-kappab-activating complex engaged drug escape/resistance-conferring pathway pi3k/akt/gab1 signaling pathway alk-driven tki-treated nsclcs specific drug-resistant mutations/alterations adaptive drug-resistant escape growth-factor-driven resistance article download pdf cellular reprogramming involved tgfβ-il6-gp130-jak2 axis trk fusion-positive cancers full access small-cell lung carcinoma oncogene-driven solid cancers single-cell analysis reveals egfr-mutant lung cancers small-cell lung cancer small-cell lung cancer prepare oligonucleotide-conjugated antibodies hepatocyte growth factor egfr-mutant lung adenocarcinoma hormone-resistant breast cancer anti-egfr monoclonal antibody tumour micro-environment heterogeneity egfr-mutant lung cancer real-world clinical practice mitochondrial priming resistance-conferring genetic alterations drug-resistant cell population bcl-2/bcl-xl �drug-resisting” survivor cells genotype-matched targeted therapy cell-free tumor dna braf-mutant colorectal cancer microfluidics-based capture techniques mutant-selective allosteric inhibitors braf v600-positive advanced acquired drug-resistant progression generation tki-treated nsclcs originally drug-sensitive cells drug-resistant mutant form predict long-term outcome advanced egfr mutation-positive sclc-transformed egfr mutants acquired drug-resistant clones linking intratumoral heterogeneity early-phase “acquired” resistance standard egfr-tki group

Schema {🗺️}

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         headline:Emerging insights of tumor heterogeneity and drug resistance mechanisms in lung cancer targeted therapy
         description:The biggest hurdle to targeted cancer therapy is the inevitable emergence of drug resistance. Tumor cells employ different mechanisms to resist the targeting agent. Most commonly in EGFR-mutant non-small cell lung cancer, secondary resistance mutations on the target kinase domain emerge to diminish the binding affinity of first- and second-generation inhibitors. Other alternative resistance mechanisms include activating complementary bypass pathways and phenotypic transformation. Sequential monotherapies promise to temporarily address the problem of acquired drug resistance, but evidently are limited by the tumor cells’ ability to adapt and evolve new resistance mechanisms to persist in the drug environment. Recent studies have nominated a model of drug resistance and tumor progression under targeted therapy as a result of a small subpopulation of cells being able to endure the drug (minimal residual disease cells) and eventually develop further mutations that allow them to regrow and become the dominant population in the therapy-resistant tumor. This subpopulation of cells appears to have developed through a subclonal event, resulting in driver mutations different from the driver mutation that is tumor-initiating in the most common ancestor. As such, an understanding of intratumoral heterogeneity—the driving force behind minimal residual disease—is vital for the identification of resistance drivers that results from branching evolution. Currently available methods allow for a more comprehensive and holistic analysis of tumor heterogeneity in that issues associated with spatial and temporal heterogeneity can now be properly addressed. This review provides some background regarding intratumoral heterogeneity and how it leads to incomplete molecular response to targeted therapies, and proposes the use of single-cell methods, sequential liquid biopsy, and multiregion sequencing to discover the link between intratumoral heterogeneity and early adaptive drug resistance. In summary, minimal residual disease as a result of intratumoral heterogeneity is the earliest form of acquired drug resistance. Emerging technologies such as liquid biopsy and single-cell methods allow for studying targetable drivers of minimal residual disease and contribute to preemptive combinatorial targeting of both drivers of the tumor and its minimal residual disease cells.
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      headline:Emerging insights of tumor heterogeneity and drug resistance mechanisms in lung cancer targeted therapy
      description:The biggest hurdle to targeted cancer therapy is the inevitable emergence of drug resistance. Tumor cells employ different mechanisms to resist the targeting agent. Most commonly in EGFR-mutant non-small cell lung cancer, secondary resistance mutations on the target kinase domain emerge to diminish the binding affinity of first- and second-generation inhibitors. Other alternative resistance mechanisms include activating complementary bypass pathways and phenotypic transformation. Sequential monotherapies promise to temporarily address the problem of acquired drug resistance, but evidently are limited by the tumor cells’ ability to adapt and evolve new resistance mechanisms to persist in the drug environment. Recent studies have nominated a model of drug resistance and tumor progression under targeted therapy as a result of a small subpopulation of cells being able to endure the drug (minimal residual disease cells) and eventually develop further mutations that allow them to regrow and become the dominant population in the therapy-resistant tumor. This subpopulation of cells appears to have developed through a subclonal event, resulting in driver mutations different from the driver mutation that is tumor-initiating in the most common ancestor. As such, an understanding of intratumoral heterogeneity—the driving force behind minimal residual disease—is vital for the identification of resistance drivers that results from branching evolution. Currently available methods allow for a more comprehensive and holistic analysis of tumor heterogeneity in that issues associated with spatial and temporal heterogeneity can now be properly addressed. This review provides some background regarding intratumoral heterogeneity and how it leads to incomplete molecular response to targeted therapies, and proposes the use of single-cell methods, sequential liquid biopsy, and multiregion sequencing to discover the link between intratumoral heterogeneity and early adaptive drug resistance. In summary, minimal residual disease as a result of intratumoral heterogeneity is the earliest form of acquired drug resistance. Emerging technologies such as liquid biopsy and single-cell methods allow for studying targetable drivers of minimal residual disease and contribute to preemptive combinatorial targeting of both drivers of the tumor and its minimal residual disease cells.
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      dateModified:2019-12-09T00:00:00Z
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         Tumor heterogeneity
         Acquired drug resistance
         Adaptive evolution
         Minimal residual disease
         Oncology
         Hematology
         Cancer Research
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      name:Penn State Cancer Institute, Penn State Health Milton S. Hershey Medical Center, Penn State University, Hershey, USA

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