Combined effect of cabozantinib and gefitinib in crizotinib-resistant lung tumors harboring ROS1 fusions.
Combined effect of cabozantinib and gefitinib in crizotinib-resistant lung tumors harboring ROS1 fusions.
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DOI：
10.1111/cas.13752
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发表时间：
2018-10
期刊：
影响因子：
5.7
通讯作者：
Kiura K
中科院分区：
文献类型：
--
作者：
Kato Y;Ninomiya K;Ohashi K;Tomida S;Makimoto G;Watanabe H;Kudo K;Matsumoto S;Umemura S;Goto K;Ichihara E;Ninomiya T;Kubo T;Sato A;Hotta K;Tabata M;Toyooka S;Maeda Y;Kiura K
ROS1酪氨酸激酶抑制剂（TKI）克里唑替尼对携带ROS1融合基因的非小细胞肺癌（NSCLC）患者有显著的疗效。然而，患者不可避免地会对这种药物产生耐药性。因此，ROS1融合基因肺肿瘤需要新的治疗策略。在本研究中，我们将携带SLC34A2‐ROS1的HCC78和携带CD74‐ROS1的ABC‐20肺癌细胞系作为基于细胞系的耐药模型。从HCC78中建立耐克唑替尼HCC78R细胞。我们使用荧光受体酪氨酸激酶阵列和下一代测序的RNA序列分析全面筛选耐药细胞。HCC78R细胞显示HB‐EGF上调，表皮生长因子受体（EGFR）磷酸化和EGFR信号通路激活。重组HB‐EGF或EGF使HCC78细胞或ABC‐20细胞对克唑替尼产生耐药性。下一代测序的RNA序列分析显示，AXL在HCC78R细胞中上调。体外实验显示，HCC78R细胞对EGFR - TKI或抗EGFR抗体具有明显的敏感性。AXL抑制剂cabozantinib或gilteritinib与EGFR - TKI联合治疗对HCC78R细胞比单独使用EGFR - TKI或AXL抑制剂更有效。卡博赞替尼联合吉非替尼可有效抑制NOG小鼠体内异种移植模型中HCC78R肿瘤的生长。本研究结果表明，HB‐EGF/EGFR和AXL在含有ROS1融合的肺癌的克里唑替尼耐药中发挥作用。对于携带ROS1融合基因的晚期NSCLC患者，cabozantinib联合EGFR - TKI可能是一种有用的替代治疗策略。
The ROS1 tyrosine kinase inhibitor (TKI) crizotinib has shown dramatic effects in patients with non‐small cell lung cancer (NSCLC) harboring ROS1 fusion genes. However, patients inevitably develop resistance to this agent. Therefore, a new treatment strategy is required for lung tumors with ROS1 fusion genes. In the present study, lung cancer cell lines, HCC78 harboring SLC34A2‐ROS1 and ABC‐20 harboring CD74‐ROS1, were used as cell line‐based resistance models. Crizotinib‐resistant HCC78R cells were established from HCC78. We comprehensively screened the resistant cells using a phosphor‐receptor tyrosine kinase array and RNA sequence analysis by next‐generation sequencing. HCC78R cells showed upregulation of HB‐EGF and activation of epidermal growth factor receptor (EGFR) phosphorylation and the EGFR signaling pathway. Recombinant HB‐EGF or EGF rendered HCC78 cells or ABC‐20 cells resistant to crizotinib. RNA sequence analysis by next‐generation sequencing revealed the upregulation of AXL in HCC78R cells. HCC78R cells showed marked sensitivity to EGFR‐TKI or anti‐EGFR antibody treatment in vitro. Combinations of an AXL inhibitor, cabozantinib or gilteritinib, and an EGFR‐TKI were more effective against HCC78R cells than monotherapy with an EGFR‐TKI or AXL inhibitor. The combination of cabozantinib and gefitinib effectively inhibited the growth of HCC78R tumors in an in vivo xenograft model of NOG mice. The results of this study indicated that HB‐EGF/EGFR and AXL play roles in crizotinib resistance in lung cancers harboring ROS1 fusions. The combination of cabozantinib and EGFR‐TKI may represent a useful alternative treatment strategy for patients with advanced NSCLC harboring ROS1 fusion genes.
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DOI：
10.1158/1078-0432.ccr-12-0550
发表时间：
2012-09-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Davies KD;Le AT;Theodoro MF;Skokan MC;Aisner DL;Berge EM;Terracciano LM;Cappuzzo F;Incarbone M;Roncalli M;Alloisio M;Santoro A;Camidge DR;Varella-Garcia M;Doebele RC
通讯作者：
Doebele RC
DOI：
10.1158/1078-0432.ccr-14-1385
发表时间：
2015-01-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Katayama R;Kobayashi Y;Friboulet L;Lockerman EL;Koike S;Shaw AT;Engelman JA;Fujita N
通讯作者：
Fujita N
影响因子：
3
作者：
Wakelee HA;Gettinger S;Engelman J;Jänne PA;West H;Subramaniam DS;Leach J;Wax M;Yaron Y;Miles DR;Lara PN Jr
通讯作者：
Lara PN Jr
影响因子：
51.1
作者：
Drilon, Alexander;Rekhtman, Natasha;Arcila, Maria;Wang, Lu;Ni, Andy;Albano, Melanie;Van Voorthuysen, Martine;Somwar, Romel;Smith, Roger S.;Montecalvo, Joseph;Plodkowski, Andrew;Ginsberg, Michelle S.;Riely, Gregory J.;Rudin, Charles M.;Ladanyi, Marc;Kris, Mark G.
通讯作者：
Kris, Mark G.
影响因子：
5.7
作者：
Mizuuchi, Hiroshi;Suda, Kenichi;Mitsudomi, Tetsuya
通讯作者：
Mitsudomi, Tetsuya