治療抵抗性小細胞肺がんにおけるケモカインネットワークを標的とした新規治療の開発

金沢大学がん進展制御研究所原発性肺がんの約15%を占める小細胞肺がんは、プラチナ併用化学療法が高い奏効率を示すが、速やかに耐性化する治療抵抗性のがんである。本研究ではSCLCの治療抵抗性にケモカインネットワークが強く関与しているという仮説を検証し、これを標的とした新たな治療開発を行うことを目的とする。申請者はケモカインであるCCL2の産生を増加させる転写因子であるFOXK1の発現上昇が、SCLCの標準化学療法Cisplatinに対するアポトーシス抵抗性に関連があることを新たに見出した。この結果から、FOXK1-CCL2-CCR2経路の活性化がSCLCにおけるCDDP耐性の原因として着目し、本研究を計画した。肺がんはわが国の悪性新生物の死因の第一位であるが、分子標的薬あるいは免疫療法の開発が急速に進んでいる。特に非小細胞肺がん (以下、NSCLC) においては分子標的薬に対する薬剤耐性機構が徐々に明らかにされている一方で、小細胞肺がん (以下、SCLC) に関しては30年以上もの間、プラチナ併用化学療法 (CDDP or CBDCA + VP-16療法) が一次治療として確立していたが、バイオマーカーを基にした分子標的薬の開発は成功していない。今年、本邦にて免疫チェックポイント阻害薬 (抗PD-L1抗体) であるAtezolizumabをプラチナ併用化学療法に追加する一次治療が保険承認されたが、全生存期間中央値はわずか2カ月程度しか延長せず、NSCLCと比較しても免疫療法の効果は不十分である (Horn L et al. N Engl J Med 2018) 。また、プラチナ併用化学療法に対し速やかに抵抗性となった再発SCLC (refractory relapse) に対してはNGTあるいはAMR単剤が実施されるが、いずれも全生存期間中央値は約6ヶ月と不良 (Pawel J et al. J Clin Oncol 2014) であり、有効な治療が確立されていない。本研究ではSCLCの治療抵抗性にケモカインネットワークが強く関与しているという仮説を検証し、これを標的とした新たな治療開発を行うことを目的とする。申請者はケモカインであるCCL2の産生を増加させる転写因子であるFOXK1の発現上昇が、SCLCの標準化学療法 Cisplatin (以下、CDDP) に対するアポトーシス抵抗性に関連があることを新たに見出した。この結果から、FOXK1-CCL2-CCR2経路の活性化がSCLCにおけるCDDP耐性の原因として着目し、本研究を進めている。研究課題/領域番号:20K17178, 研究期間(年度):2020-04-01 – 2021-03-31出典：研究課題「治療抵抗性小細胞肺がんにおけるケモカインネットワークを標的とした新規治療の開発」課題番号20K17178（KAKEN：科学研究費助成事業データベース（国立情報学研究所）） （https://kaken.nii.ac.jp/ja/grant/KAKENHI-PROJECT-20K17178/）を加工して作

Receptor ligand-triggered resistance to alectinib and its circumvention by Hsp90 inhibition in EML4-ALK lung cancer cells

13301甲第4098号博士（医学）金沢大学博士論文本文Full 以下に掲載：Oncotarget 5(13) pp.4920-1928 2014. Creative Commons. 共著者：Azusa Tanimoto, Tadaaki Yamada, Shigeki Nanjo, Shinji Takeuchi, Hiromichi Ebi, Kenji Kita, Kunio Matsumoto, Seiji Yan

The impact of targeting TRAF2 and NCK-interacting protein kinase (TNIK) on anti-tumor effect in small cell lung cancer

View full abstracthttps://openworks.mdanderson.org/leading-edge/1056/thumbnail.jp

Resminostat in EGFR-mutated lung cancer

Drug-tolerant cells are mediators of acquired resistance. BIM-intron2 deletion polymorphism (BIM-del) is one of the mechanisms underlying the resistance to epidermal growth factor tyrosine kinase inhibitor (EGFR-TKI)-mediated apoptosis that induces drug tolerance. Here, we investigated whether resminostat, a histone deacetylase inhibitor, circumvents BIM-del-associated apoptosis resistance. The human EGFR-mutated non-small cell lung cancer (NSCLC) cell line PC-9 and its homozygous BIM-del-positive variant (PC-9 BIMi2-/-), established by editing with zinc finger nuclease, were used. In comparison with PC-9 cells, PC-9 BIMi2-/- cells were less sensitive to apoptosis mediated by EGFR-TKIs such as gefitinib and osimertinib. The combined use of resminostat and an EGFR-TKI preferentially induced the expression of the pro-apoptotic BIM transcript containing exon 4 rather than that containing exon 3, increased the level of pro-apoptotic BIM protein (BIMEL), and stimulated apoptosis in vitro. In a subcutaneous tumor model derived from PC-9 BIMi2-/- cells, gefitinib monotherapy decreased tumor size but retained residual lesions, indicative of the presence of tolerant cells in tumors. The combined use of resminostat and gefitinib increased BIMEL protein level and induced apoptosis, subsequently leading to the remarkable shrinkage of tumor. These findings suggest the potential of resminostat to circumvent tolerance to EGFR-TKIs associated with BIM deletion polymorphism

Receptor ligand-triggered resistance to alectinib and its circumvention by Hsp90 inhibition in EML4-ALK lung cancer cells

Alectinib is a new generation ALK inhibitor with activity against the gatekeeper L1196M mutation that showed remarkable activity in a phase I/II study with echinoderm microtubule associated protein-like 4 (EML4) - anaplastic lymphoma kinase (ALK) non-small cell lung cancer (NSCLC) patients. However, alectinib resistance may eventually develop. Here, we found that EGFR ligands and HGF, a ligand of the MET receptor, activate EGFR and MET, respectively, as alternative pathways, and thereby induce resistance to alectinib. Additionally, the heat shock protein 90 (Hsp90) inhibitor suppressed protein expression of ALK, MET, EGFR, and AKT, and thereby induced apoptosis in EML4-ALK NSCLC cells, even in the presence of EGFR ligands or HGF. These results suggest that Hsp90 inhibitors may overcome ligand-triggered resistance to new generation ALK inhibitors and may result in more successful treatment of NSCLC patients with EML4-ALK

Validating DLL3-targeting CAR T in small cell lung cancer

View full abstracthttps://openworks.mdanderson.org/leading-edge/1022/thumbnail.jp

AXL confers intrinsic resistance to osimertinib and advances the emergence of tolerant cells

A novel EGFR-tyrosine kinase inhibitor (TKI), osimertinib, has marked efficacy in patients with EGFR-mutated lung cancer. However, some patients show intrinsic resistance and an insufficient response to osimertinib. This study showed that osimertinib stimulated AXL by inhibiting a negative feedback loop. Activated AXL was associated with EGFR and HER3 in maintaining cell survival and inducing the emergence of cells tolerant to osimertinib. AXL inhibition reduced the viability of EGFR-mutated lung cancer cells overexpressing AXL that were exposed to osimertinib. The addition of an AXL inhibitor during either the initial or tolerant phases reduced tumor size and delayed tumor re-growth compared to osimertinib alone. AXL was highly expressed in clinical specimens of EGFR-mutated lung cancers and its high expression was associated with a low response rate to EGFR-TKI. These results indicated pivotal roles for AXL and its inhibition in the intrinsic resistance to osimertinib and the emergence of osimertinib-tolerant cells

Transient IGF-1R inhibition combined with osimertinib eradicates AXL-low expressing EGFR mutated lung cancer

Drug tolerance is the basis for acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) including osimertinib, through mechanisms that still remain unclear. Here, we show that while AXL-low expressing EGFR mutated lung cancer (EGFRmut-LC) cells are more sensitive to osimertinib than AXL-high expressing EGFRmut-LC cells, a small population emerge osimertinib tolerance. The tolerance is mediated by the increased expression and phosphorylation of insulin-like growth factor-1 receptor (IGF-1R), caused by the induction of its transcription factor FOXA1. IGF-1R maintains association with EGFR and adaptor proteins, including Gab1 and IRS1, in the presence of osimertinib and restores the survival signal. In AXL-low-expressing EGFRmut-LC cell-derived xenograft and patient-derived xenograft models, transient IGF-1R inhibition combined with continuous osimertinib treatment could eradicate tumors and prevent regrowth even after the cessation of osimertinib. These results indicate that optimal inhibition of tolerant signals combined with osimertinib may dramatically improve the outcome of EGFRmut-LC