The Minority Report: Targeting the Rare Oncogenes in NSCLC

McCoach, Caroline E.

doi:10.1007/s11864-014-0310-8

Cited by 14 publications

(15 citation statements)

References 70 publications

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“…Approximately 1.3 million new cases of non-small-cell lung cancer (NSCLC) patients are identified each year, comprising 80% of primary lung cancers (McCoach and Doebele, 2014). The prognosis for advanced and metastatic NSCLC patients is poor (Jemal et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

KIF5B-RET Oncoprotein Signals through a Multi-kinase Signaling Hub

Das

Cagan

2017

Cell Reports

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Summary Gene fusions are increasingly recognized as important cancer drivers. KIF5B-RET gene was recently identified as a primary driver in a subset of lung adenocarcinomas. Targeting human KIF5B-RET to epithelia in Drosophila directed multiple aspects of transformation including hyperproliferation, epithelial-to-mesenchymal transition, invasion, and extension of striking invadopodia-like processes. KIF5B-RET-transformed human bronchial cell line showed similar aspects of transformation including invadopodia-like processes. Through a combination of genetic and biochemical studies we demonstrate that the kinesin and kinase domains of KIF5B-RET act together to establish an emergent microtubule and RAB vesicle-dependent RET-SRC-EGFR-FGFR ‘signaling hub’. We demonstrate that drugs designed to inhibit RET alone work poorly in KIF5B-RET-transformed cells. However, combining the RET inhibitor sorafenib with drugs that target EGFR or microtubules or FGFR led to strong efficacy in both Drosophila and human cell line KIF5B-RET models. This work demonstrates the utility in exploring the full biology of fusions to identify rational therapeutic strategies.

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Section: Introductionmentioning

confidence: 99%

KIF5B-RET Oncoprotein Signals through a Multi-kinase Signaling Hub

Das

Cagan

2017

Cell Reports

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“…75 In summary, targeted therapies offer the opportunity to target specific genetic driver alterations, but they have limitations. Known mutations are not present in many cases: genetic changes have been identified in patients with non-squamous NSCLC, while EGFR and ALK mutations are rarely seen in squamous NSCLC.…”

Section: Review Lung Cancermentioning

confidence: 99%

Immunotherapy and Targeted Therapies in the Treatment of Non-small Cell Lung Cancer

Nguyen-Ngoc¹,

Reck²,

Tan³

et al. 2017

European Oncology &Amp; Haematology

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In the last decade, the emergence of targeted therapies has changed the treatment paradigm for non-small cell lung cancer (NSCLC). The growing availability of therapies targeting specific genetic alterations, such as epidermal growth factor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements, have led to changes in the guidelines to reflect the need for molecular profiling. More recently, immunotherapeutic approaches have been investigated in the treatment setting of NSCLC, and these may provide superior outcomes and have substantially better tolerability compared to chemotherapy. Immunotherapies currently available for NSCLC include the checkpoint inhibitors anti-PD-1 antibodies nivolumab and pembrolizumab. Several other anti-PD-L1 compounds such as atezolizumab, durvalumab and avelumab are also very advanced in clinical investigation, in monotherapy as well as in combination with immune priming phase activators anti-CTLA4 ipilimumab and tremelimumab, across all treatment lines. The challenge facing oncologists is identifying which therapy is best suited to the individual patient.

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“…These include ROS1 fusions, RET fusions, neurotrophic tyrosine kinase receptor type 1 (NTFK1) fusions, Met gene amplification, FGFR1 gene amplification, HER2 mutations. 88 Amplification of mesenchymal-epithelial transition (MET) factor is found in about 5% of lung adenocarcinoma. Promising data were obtained from two phase II trials, one investigating dual EGFR and MET inhibition, with erlotinib and tivantinib,the monoclonal antibody onartuzumab.…”

Section: Other Molecular Driver Targetsmentioning

confidence: 99%

“…88 Despite demonstrating impressive efficacy, targeted therapies have limitations. In many cases, known mutations are not present: squamous NSCLC rarely have EGFR and ALK mutations.…”

Section: Other Molecular Driver Targetsmentioning

confidence: 99%

Advancing the Management of Non-small Cell Lung Cancer

Fakih¹

2017

European Oncology &Amp; Haematology

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A dvances in the development of targeted therapies and immunotherapy have transformed the management of non small-cell lung cancer (NSCLC). Targeting angiogenesis and molecular drivers of carcinogenesis has led to the approval of several new therapies. More recently, immunotherapeutic approaches have been investigated in the treatment setting of NSCLC. These include immune checkpoint inhibitors (e.g. anti-cytotoxic T-lymphocyte antigen-4 [CTLA-4], anti-programmed death-1 (PD-1) and anti-programmed deathligand 1 [PD-L1] agents). The emergence of so many therapeutic options offers the potential for personalised therapy. Molecular profiling can inform treatment decisions but there is a need for more data to determine the optimal sequencing and combination of targeted and immunotherapeutic agents.

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The Minority Report: Targeting the Rare Oncogenes in NSCLC

Cited by 14 publications

References 70 publications

KIF5B-RET Oncoprotein Signals through a Multi-kinase Signaling Hub

KIF5B-RET Oncoprotein Signals through a Multi-kinase Signaling Hub

Immunotherapy and Targeted Therapies in the Treatment of Non-small Cell Lung Cancer

Advancing the Management of Non-small Cell Lung Cancer

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