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Ref Type | Journal Article | ||||||||||||
PMID | (34158345) | ||||||||||||
Authors | Kano H, Ichihara E, Watanabe H, Nishii K, Ando C, Nakasuka T, Ninomiya K, Kato Y, Kubo T, Rai K, Ohashi K, Hotta K, Tabata M, Maeda Y, Kiura K | ||||||||||||
Title | SHP2 Inhibition Enhances the Effects of Tyrosine Kinase Inhibitors in Preclinical Models of Treatment-naïve ALK-, ROS1- , or EGFR -altered Non-small Cell Lung Cancer. | ||||||||||||
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Abstract Text | After molecular-targeted therapy, some cancer cells may remain that are resistant to therapies targeting oncogene alterations, such as those in the genes encoding the EGFR and anaplastic lymphoma kinase ( ALK ) as well as c-ros oncogene 1 ( ROS1 ). The mechanisms underlying this type of resistance are unknown. In this article, we report the potential role of Src homology 2 domain-containing phosphatase 2 (SHP2) in the residual cells of ALK / ROS1 / EGFR- altered non-small cell lung cancer (NSCLC). Molecular-targeted therapies failed to inhibit the ERK signaling pathway in the residual cells, whereas the SHP2 inhibitor SHP099 abolished their remaining ERK activity. SHP099 administered in combination with molecular-targeted therapy resulted in marked growth inhibition of cancer cells both in vitro and in vivo Thus, treatment combining an SHP2 inhibitor and a tyrosine kinase inhibitor may be a promising therapeutic strategy for oncogene-driven NSCLC. |
Molecular Profile | Treatment Approach |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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Gene | Variant | Impact | Protein Effect | Variant Description | Associated with drug Resistance |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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EML4 - ALK | lung non-small cell carcinoma | sensitive | Alectinib + Selumetinib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, the combination of Alecensa (alectinib) and Koselugo (selumetinib) inhibited tumor growth in cell line xenograft models of non-small cell lung cancer harboring EML4-ALK, but was less potent compared to treatment with the combination of Alecensa (alectinib) and SHP099 (PMID: 34158345). | 34158345 |
EML4 - ALK | lung non-small cell carcinoma | sensitive | Alectinib + SHP099 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, the combination of Alecensa (alectinib) and SHP099 inhibited downstream signaling and synergistically inhibited proliferation in non-small cell lung cancer cell lines harboring EML4-ALK in culture, and resulted in increased suppression of tumor growth in cell line xenograft models compared to either agent alone (PMID: 34158345). | 34158345 |
EML4 - ALK | lung non-small cell carcinoma | sensitive | Alectinib + RMC-4550 | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of Alecensa (alectinib) and RMC-4550 inhibited cell growth and downstream signaling in non-small cell lung cancer cell lines harboring EML4-ALK in culture (PMID: 34158345). | 34158345 |