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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 epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) as well as c-ros oncogene 1 (ROS1). The mechanisms underlying this type of resistance are unknown. Here 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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Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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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 |