Supplementary Figure 2 from 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

Kano, Hirohisa; Ichihara, Eiki; Watanabe, Hiromi; Nishii, Kazuya; Ando, Chihiro; Nakasuka, Takamasa; Ninomiya, Kiichiro; Kato, Yuka; Kubo, Toshio; Rai, Kammei; Ohashi, Kadoaki; Hotta, Katsuyuki; Tabata, Masahiro; Maeda, Yoshinobu; Kiura, Katsuyuki

doi:10.1158/1535-7163.22522927.v1

Supplementary Figure 2 from 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

journal contribution

posted on 2023-04-03, 18:48 authored by Hirohisa Kano, Eiki Ichihara, Hiromi Watanabe, Kazuya Nishii, Chihiro Ando, Takamasa Nakasuka, Kiichiro Ninomiya, Yuka Kato, Toshio Kubo, Kammei Rai, Kadoaki Ohashi, Katsuyuki Hotta, Masahiro Tabata, Yoshinobu Maeda, Katsuyuki Kiura

Supplementary Figure 2. ROS1 TKI in combination with SHP099 (A) Immunoblots of the indicated proteins in HCC78 and ABC-20 cells treated for 24 h with DS-6051b (Ds, 100 nM) with or without SHP099 (SHP, 5 µM). Comb, combination. (B) RAS-GTP assay in H3122 cells treated with alectinib (Alec, 100 nM), ABC-20 cells treated with crizotinib (Cri, 1 µM) and HCC827 cells treated with osimertinib (Osi, 100 nM) for 24 h. All cell lines were also treated or not with SHP099 (SHP, 5 µM). Comb, combination. (C) Cell viability curves for cell lines treated with DS-6051b (DS) alone (circles), SHP099 (SHP) alone (triangles) or DC6051b and SHP099 (5 µM) (squares). All drugs were loaded for 96 h. Error bars represent the standard error.

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ARTICLE ABSTRACT

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.