PMID- 34158345 OWN - NLM STAT- MEDLINE DCOM- 20220210 LR - 20220210 IS - 1538-8514 (Electronic) IS - 1535-7163 (Linking) VI - 20 IP - 9 DP - 2021 Sep TI - SHP2 Inhibition Enhances the Effects of Tyrosine Kinase Inhibitors in Preclinical Models of Treatment-naive ALK-, ROS1-, or EGFR-altered Non-small Cell Lung Cancer. PG - 1653-1662 LID - 10.1158/1535-7163.MCT-20-0965 [doi] AB - 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. CI - (c)2021 American Association for Cancer Research. FAU - Kano, Hirohisa AU - Kano H AD - Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan. FAU - Ichihara, Eiki AU - Ichihara E AD - Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan. ichiha-e@md.okayama-u.ac.jp. FAU - Watanabe, Hiromi AU - Watanabe H AD - Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan. FAU - Nishii, Kazuya AU - Nishii K AD - Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan. FAU - Ando, Chihiro AU - Ando C AD - Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan. FAU - Nakasuka, Takamasa AU - Nakasuka T AD - Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan. FAU - Ninomiya, Kiichiro AU - Ninomiya K AD - Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan. FAU - Kato, Yuka AU - Kato Y AD - Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan. FAU - Kubo, Toshio AU - Kubo T AD - Center for Clinical Oncology, Okayama University Hospital, Okayama, Japan. FAU - Rai, Kammei AU - Rai K AD - Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan. FAU - Ohashi, Kadoaki AU - Ohashi K AUID- ORCID: 0000-0002-5180-3933 AD - Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan. FAU - Hotta, Katsuyuki AU - Hotta K AD - Center for Innovative Clinical Medicine, Okayama University Hospital, Okayama, Japan. FAU - Tabata, Masahiro AU - Tabata M AD - Center for Clinical Oncology, Okayama University Hospital, Okayama, Japan. FAU - Maeda, Yoshinobu AU - Maeda Y AD - Department of Hematology, Oncology and Respiratory Medicine, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan. FAU - Kiura, Katsuyuki AU - Kiura K AUID- ORCID: 0000-0002-9172-9379 AD - Department of Allergy and Respiratory Medicine, Okayama University Hospital, Okayama, Japan. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20210622 PL - United States TA - Mol Cancer Ther JT - Molecular cancer therapeutics JID - 101132535 RN - 0 (Biomarkers, Tumor) RN - 0 (Piperidines) RN - 0 (Protein Kinase Inhibitors) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Pyrimidines) RN - 0 (SHP099) RN - EC 2.7.10.1 (ALK protein, human) RN - EC 2.7.10.1 (Anaplastic Lymphoma Kinase) RN - EC 2.7.10.1 (EGFR protein, human) RN - EC 2.7.10.1 (ErbB Receptors) RN - EC 2.7.10.1 (Protein-Tyrosine Kinases) RN - EC 2.7.10.1 (ROS1 protein, human) RN - EC 3.1.3.48 (PTPN11 protein, human) RN - EC 3.1.3.48 (Protein Tyrosine Phosphatase, Non-Receptor Type 11) SB - IM MH - Anaplastic Lymphoma Kinase/*genetics MH - Animals MH - Apoptosis MH - Biomarkers, Tumor/genetics MH - Carcinoma, Non-Small-Cell Lung/*drug therapy/genetics/pathology MH - Cell Proliferation MH - Drug Synergism MH - Drug Therapy, Combination MH - ErbB Receptors/genetics MH - Female MH - Gene Expression Regulation, Neoplastic MH - Gene Rearrangement MH - Humans MH - Lung Neoplasms/drug therapy/genetics/pathology MH - Mice MH - Mice, Inbred BALB C MH - Mice, Nude MH - Piperidines/*pharmacology MH - Protein Kinase Inhibitors/*pharmacology MH - Protein Tyrosine Phosphatase, Non-Receptor Type 11/*antagonists & inhibitors MH - Protein-Tyrosine Kinases/*genetics MH - Proto-Oncogene Proteins/*genetics MH - Pyrimidines/*pharmacology MH - Tumor Cells, Cultured MH - Xenograft Model Antitumor Assays EDAT- 2021/06/24 06:00 MHDA- 2022/02/11 06:00 CRDT- 2021/06/23 06:40 PHST- 2020/11/16 00:00 [received] PHST- 2021/03/26 00:00 [revised] PHST- 2021/06/11 00:00 [accepted] PHST- 2021/06/24 06:00 [pubmed] PHST- 2022/02/11 06:00 [medline] PHST- 2021/06/23 06:40 [entrez] AID - 1535-7163.MCT-20-0965 [pii] AID - 10.1158/1535-7163.MCT-20-0965 [doi] PST - ppublish SO - Mol Cancer Ther. 2021 Sep;20(9):1653-1662. doi: 10.1158/1535-7163.MCT-20-0965. Epub 2021 Jun 22.