A focal adhesion kinase-YAP signaling axis drives drug tolerant persister cells and residual disease in lung cancer

Targeted therapy is effective in many tumor types including lung cancer, the leading cause of cancer mortality. Paradigm defining examples are targeted therapies directed against non-small cell lung cancer (NSCLC) subtypes with oncogenic alterations in EGFR, ALK and KRAS. The success of targeted therapy is limited by drug-tolerant tumor cells which withstand and adapt to treatment and comprise the residual disease state that is typical during treatment with clinical targeted therapies. Here, we integrate studies in patient-derived and immunocompetent lung cancer models and clinical specimens obtained from patients on targeted therapy to uncover a focal adhesion kinase (FAK)-YAP signaling axis that promotes residual disease during oncogenic EGFR-, ALK-, and KRAS-targeted therapies. FAK-YAP signaling inhibition combined with the primary targeted therapy suppressed residual drug-tolerant cells and enhanced tumor responses. This study unveils a FAK-YAP signaling module that promotes residual disease in lung cancer and mechanism-based therapeutic strategies to improve tumor response.

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Vimentin regulates lung cancer cell adhesion through a VAV2–Rac1 pathway to control focal adhesion kinase activity

Oncogene ◽

10.1038/onc.2014.123 ◽

2014 ◽

Vol 34 (15) ◽

pp. 1979-1990 ◽

Cited By ~ 82

Author(s):

L S Havel ◽

E R Kline ◽

A M Salgueiro ◽

A I Marcus

Keyword(s):

Lung Cancer ◽

Cell Adhesion ◽

Focal Adhesion Kinase ◽

Cancer Cell ◽

Focal Adhesion ◽

Kinase Activity ◽

Lung Cancer Cell ◽

Cancer Cell Adhesion ◽

Focal Adhesion Kinase Activity

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Emerging insights of tumor heterogeneity and drug resistance mechanisms in lung cancer targeted therapy

Journal of Hematology & Oncology ◽

10.1186/s13045-019-0818-2 ◽

2019 ◽

Vol 12 (1) ◽

Cited By ~ 22

Author(s):

Zuan-Fu Lim ◽

Patrick C. Ma

Keyword(s):

Lung Cancer ◽

Drug Resistance ◽

Targeted Therapy ◽

Minimal Residual Disease ◽

Tumor Heterogeneity ◽

Residual Disease ◽

Resistance Mechanisms ◽

Intratumoral Heterogeneity ◽

Acquired Drug Resistance ◽

Minimal Residual

AbstractThe 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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Abstract LB-B02: Acquisition of stem cell-like properties accompanying with Src family kinase/Focal adhesion kinase activation contributes to acquired resistance to afatinib in lung cancer cells

10.1158/1535-7163.targ-15-lb-b02 ◽

2015 ◽

Author(s):

Yuichi Murakami ◽

Kahori Sonoda ◽

Koichi Azuma ◽

Kosuke Watari ◽

Michihiko Kuwano ◽

...

Keyword(s):

Lung Cancer ◽

Stem Cell ◽

Focal Adhesion Kinase ◽

Cancer Cells ◽

Focal Adhesion ◽

Acquired Resistance ◽

Lung Cancer Cells ◽

Src Family Kinase ◽

Kinase Activation

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The Netrin-1-Neogenin-1 signaling axis controls neuroblastoma cell migration via integrin-β1 and focal adhesion kinase activation

Cell Adhesion & Migration ◽

10.1080/19336918.2021.1892397 ◽

2021 ◽

Vol 15 (1) ◽

pp. 58-73

Author(s):

Andrea A. Villanueva ◽

Pilar Sanchez-Gomez ◽

Ernesto Muñoz-Palma ◽

Sofía Puvogel ◽

Bárbara S. Casas ◽

...

Keyword(s):

Cell Migration ◽

Focal Adhesion Kinase ◽

Focal Adhesion ◽

Neuroblastoma Cell ◽

Integrin Β1 ◽

Kinase Activation ◽

Signaling Axis

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Matching insurance claims data with EMR molecular status data in non-small cell lung cancer (NSCLC) patients: Understanding real-world molecular testing and prevalence rates at the site and investigator level.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e20568 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e20568-e20568

Author(s):

Michael Gregory Cushion ◽

Bhavani Krishnan ◽

Jeff Paul Hodge ◽

Jaya Chandra Balusu ◽

Joseph Wagner ◽

...

Keyword(s):

Lung Cancer ◽

Clinical Trials ◽

Targeted Therapy ◽

Real World ◽

Targeted Therapies ◽

Claims Data ◽

Molecular Testing ◽

Insurance Claims ◽

Insurance Claims Data ◽

Nsclc Patients

e20568 Background: Many targeted therapy clinical trials require a somatic gene mutation/alteration for eligibility. We assessed the feasibility of leveraging Real-World Data (RWD) to enrol NSCLC patients into clinical trials. Methods: US insurance claims data were extracted to identify lung cancer patients. These data were matched with EMR data also containing NSCLC patients’ details regarding the occurrence and results of molecular testing for EGFR, ALK, ROS1, JAK2, HER2 and RET somatic alterations, achieving a level of granular detail beyond that available in each individual dataset. A one-year extraction period was applied, with no gender or age restrictions. Results: Results for the matched dataset are summarised in the table below - the overall patient record match was 89.6%. Conclusions: The observed prevalence correlated reasonably well with literature reported prevalence for the molecular biomarkers associated commercially available targeted therapies in NSCLC (EGFR, ALK, ROS1). The sample size for the remaining biomarkers was too small to draw conclusions, though the presence of data correlating to these is of interest, considering that there are no currently approved targeted therapies in NSCLC tailored to these predictive biomarkers. This approach could be expanded upon to recruit patients into targeted therapy clinical trials as the dataset is fully linkable to sites and investigators. With the emergence of broad genomic profiling, the availability of molecular data to support clinical trial enrolment is also expected to grow.[Table: see text]

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Early Candidate Biomarkers of Non–Small Cell Lung Cancer Are Screened and Identified in Premalignant Lung Lesions

Technology in Cancer Research & Treatment ◽

10.1177/1533034615627391 ◽

2016 ◽

Vol 16 (1) ◽

pp. 66-74 ◽

Cited By ~ 10

Author(s):

Yandong Nan ◽

Jie Du ◽

Lijie Ma ◽

Hua Jiang ◽

Faguang Jin ◽

...

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Focal Adhesion Kinase ◽

Focal Adhesion ◽

Cell Lung Cancer ◽

Src Kinase ◽

Small Cell ◽

Normal Lung ◽

Biological Processes ◽

Small Cell Lung

A specific protein profile that accompanies neoplastic transformation in the premalignant airway epithelium could provide an opportunity for early diagnosis of lung cancer. The aim of this study was to screen and identify early candidate biomarkers of non–small cell lung cancer. Thirteen non–small cell lung cancer samples were obtained within 30 minutes after a surgical resection. Laser capture microdissection was performed to enrich the normal lung cell and squamous metaplasia or atypical adenomatous hyperplasia cell populations. The resulting tandem mass spectrum was automatically searched for proteins against International Protein Index (IPI) human protein database using the TurboSEQUEST searching engine. The molecular function and biological processes of identified proteins were determined based on universal bioinformatics tools. The 2 proteins of interest, focal adhesion kinase and C-terminal Src kinase, were validated using Western blot method. A total of 863 proteins were identified by automatically searching the tandem mass spectrum, among which 427 were dysregulated expression in premalignant airway epithelium compared with those of normal lung cells. The 427 proteins were mainly distributed in 24 sorts of cellular components, 22 molecular function, 15 biological processes, and 10 significant perturbations of pathways. The most significant network included 48 genes and was related to energy production, cell cytoskeleton, cell adhesion, metabolism, oxidative stress, and small molecule biochemistry. Focal adhesion kinase and C-terminal Src kinase were significantly overexpressed in premalignant lung lesion cells compared with the normal lung cells in 13 cases. We identified that there were 427 proteins involved in non–small cell lung cancer carcinogenic process and confirmed the key biological pathways in premalignant lung tissue. The significantly upregulated focal adhesion kinase and C-terminal Src kinase could be considered as molecular biomarkers for early diagnosis and prognosis of non–small cell lung cancer.

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