体外Ponatinib耐药细胞模型建立及耐药机制研究
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摘要
慢性粒细胞白血病(Chronic myeloid leukemia, CML)是一种起源于造血干细胞恶性克隆性疾病,费城染色体(Ph)是其特征的细胞遗传学标志,其衍生的BCR-ABL融合基因编码210KD融合蛋白,后者可通过持续激活的酪氨酸激酶活化下游多条信号转导通路,促进白血病细胞增殖和凋亡耐受,从而导致慢粒的发生发展。因此,BCR-ABL酪氨酸激酶成为治疗慢粒最理想的分子靶点。伊马替尼(Imatinib)作为首个被批准用于肿瘤治疗的靶向性药物,因其治疗的安全性及有效性成为慢粒患者的一线药物。然而,仍有部分患者存在原发或是获得性耐药,其中BCR-ABL激酶结构域点突变是获得性耐药的主要原因。随后发展设计的第二代新药,尼洛替尼(Nilotinib)和达沙替尼(Dasatinib)是用于治疗Imatinib耐药或是不能耐受的慢粒患者,可抑制除T315I突变以外其它大多数的BCR-ABL激酶结构域突变所致的酪氨酸激酶活性。
Ponatinib作为治疗慢粒的第三代酪氨酸激酶抑制剂,是Ariad制药公司开发的一种可以抑制包括T315I在内的所有BCR-ABL激酶结构域突变的药物,由BCR-ABL酪氨酸激酶结构域点突变引起的Ponatinib耐药已有相关实验研究报导。目前该药已经进入Ⅱ期临床试验,该实验招募的94%CML耐药患者均为至少2种获准的酪氨酸激酶抑制剂治疗失败后,虽然经过Poantinib治疗一半的患者达到了主要细胞遗传学缓解,但仍有部分患者出现了耐药。
针对这一现象,本研究建立了体外Ponatinib耐药模型,并揭示其可能的耐药分子机制,为进一步筛选和开发新的酪氨酸激酶抑制剂,逆转Ponatinib耐药提供实验依据。
本研究使用32D (BCR-ABL)和K562两种BCR-ABL+CML细胞株,通过逐步递增Ponatinib浓度的方法建立耐药细胞株模型。以敏感细胞株为对照,PCR测序未发现其BCR-ABL激酶结构域存在点突变。用伊马替尼,尼洛替尼和达沙替尼分别处理耐药及敏感细胞株,MTS实验检测细胞增殖活性证实Ponatinib耐药的32D (BCR-ABL) ponR和K562ponR细胞,同时也存在对伊马替尼,尼洛替尼和达沙替尼耐药。Westem blot检测发现较低浓度Poantinib即可抑制耐药细胞磷酸化BCR-ABL蛋白表达。以上结果均提示耐药细胞呈现出一种非BCR-ABL酪氨酸激酶依赖的耐药分子机制。
对32D (BCR-ABL) ponR细胞进一步研究发现,在BCR-ABL活性受到抑制时,其下游底物STAT5仍保持活性。以小分子抑制剂为基础的合成性致死筛选试验结果显示只有某些JAK家族的抑制剂协同Ponatinib才会对32D (BCR-ABL) ponR耐药细胞产生合成性致死作用。shRNA敲除32D (BCR-ABL) ponR耐药细胞BCR-ABL基因模拟Ponatinib药理作用,MTS实验显示,单一JAK家族的抑制剂即可抑制耐药细胞的增殖,说明该细胞耐药与活化的JAK/STAT辅助信号转导通路有关。基因芯片技术分析耐药及敏感细胞基因表达情况,并用实时荧光定量PCR对其进行验证,发现耐药细胞中细胞因子IL-3表达明显上调(P<0.01),且IL-3中和抗体可以减弱耐药细胞对Ponatinib的耐受。而K562ponR细胞也同样存在着辅助信号转导通路MEK/ERK的活化,联合使用Ponatinib和MEK/ERK抑制剂可以抑制K562ponR细胞的生长。
我们也分析了1例经Ponatinib治疗失败的患者标本,该患者存在BCR-ABLT315I突变,但BCR-ABLT315I活性在体外可被低浓度Ponatinib抑制,合成性致死筛选试验siRNA实验发现,敲除CSF1R可协同Ponatinib显著降低白血病细胞的生长,提示其可能是通过激活CSF1R辅助信号转导通路产生的耐药。
通过这些研究说明Ponatinib耐药呈现一种非BCR-ABL依赖的耐药分子机制,针对这类患者同时采取抑制BCR-ABL及辅助信号通路抑制剂可以达到理想的治疗效果。
Chronic myeloid leukemia (CML) arises from the neoplastic transformation of a hematopoietic stem cell, which is characterized by the Philadelphia chromosome. A P210BCR-ABL protein is generated by the BCR-ABL fusion gene, which is a constitutively active tyrosine kinase that drives cell proliferation and apoptosis through multiple downstream signal pathways. Since the BCR-ABL is considered essential for the disease progression, targeting the tyrosine kinase activity of BCR-ABL shows an attractive therapeutic strategy. The BCR-ABL kinase inhibitor imatinib, because of the safety and effectivity, has become the first line therapy of CML. But still some patients show primary or acquired resistant to imatinib therapy, the most frequently described mechanism of acquired resistance to imatinb is the occurrence of point mutations in the kinase domain of BCR-ABL. Patients who are intolerant or resistant to imatinib have the effective salvage therapy of the second line ABL kinase inhibitors nilotinib and dasatinib. Both of them target most mutants except the cross resistant BCR-ABLY3151mutation.
Ponatinib, from the Ariad pharmacy company, is a multitargeted kinase inhibitor that can even inhibit BCR-ABLT3151, which is the third line therapy for patients with CML. BCR-ABL kinase domain mutation-mediated ponatinib resistance has been investigated in vitro. A pivotal phase II trial is underway, almost94%CML patients have previously failed at least2tyrosine kinase inhibitors, after ponatinib treatment half of the patients achieved major cytogenetic response, but there are still some patients resistant to ponatinib therapy.
Here, we developed ponatinib resistant, BCR-ABL positive cell lines lacking a kinase domain mutation and investigated mechanisms of resistance, trying to possibly in advance of full mechanistic understanding in the clinic, to search and investigate new tyrosine kinase inhibitor, and to restore ponatinib resistant paitent's response.
Two BCR-ABL+cell lines,32D(BCR-ABL) and K562, were exposed to escalating concentrations of ponatinib to generate ponatinib-resistant cells. BCR-ABL kinase domain sequencing of resistant cells confirmed BCR-ABL to be unmutated. MTS cell proliferation assay of sensitive and resistant cells showed that ponatinib resistant cell also exhibited resistance to imatinib, nilotinib and dasatinib. In each of the ponatinib-resistant cell lines, BCR-ABL tyrosine kinase activity was pharmacologically silenced by low concentrations of ponatinib and yet the cells survived. All data indicated a BCR-ABL kinase independent mechanism of resistance.
Based on western blot, tyrosine phosphorylation of the BCR-ABL downstream target STAT5was substantially maintained despite ponatinib-mediated inhibition of BCR-ABL1catalytic activity in32D (BCR-ABL)ponR cells. A small molecule inhibitors screen was applied to the32D(BCR-ABL)ponR resistant cell in the presence or absence of ponatinib to assess synthetic lethality. Only dual combinations of ponatinib and certain JAK inhibitors are lethal to resistant cell. Knocking down the BCR-ABL by shRNA mimicked the ponatinib effect, resistant cell exhibited single agent sensitivity to some JAK inhibitors, which suggested that JAK/STAT co-critical signaling pathway may be involved in this BCR-ABL independent mechanism of resistance. Sensitive and resistant cells were used for gene microarray analysis, and validated by the real time PCR. IL-3expression is up-regulated in resistant cell (p<0.01), and the IL-3neutralizing antibody could reduce the tolerance of resistant cell to ponatinib. Synthetic lethality screening identified MEK/ERK co-critical signaling pathway in K562ponR cells, only ponatinib synergizes with MEK/ERK inhibition to induce synthetic lethality in ponatinib resistant K562ponR cells.
We analyzed one ponatinib treatment failure patient sample recently, only BCR-ABLT3151mutation was found in this patient and BCR-ABLT3151activity was inhibited ex vivo by low concentration of ponatinib. Synthetic lethality siRNA screening showed that combination of ponatinib and knockdown CSFlR drastically reduces CML cell viability, which suggested that CSFlR co-critical signaling pathway was involved in this BCR-ABL independent mechanism of resistance.
Our findings indicate a BCR-ABL independent mechanism of ponatinib resistance, some relapsed CML patients may benefit from targeting both BCR-ABL and co-critical signaling pathways.
Ponatinib作为治疗慢粒的第三代酪氨酸激酶抑制剂,是Ariad制药公司开发的一种可以抑制包括T315I在内的所有BCR-ABL激酶结构域突变的药物,由BCR-ABL酪氨酸激酶结构域点突变引起的Ponatinib耐药已有相关实验研究报导。目前该药已经进入Ⅱ期临床试验,该实验招募的94%CML耐药患者均为至少2种获准的酪氨酸激酶抑制剂治疗失败后,虽然经过Poantinib治疗一半的患者达到了主要细胞遗传学缓解,但仍有部分患者出现了耐药。
针对这一现象,本研究建立了体外Ponatinib耐药模型,并揭示其可能的耐药分子机制,为进一步筛选和开发新的酪氨酸激酶抑制剂,逆转Ponatinib耐药提供实验依据。
本研究使用32D (BCR-ABL)和K562两种BCR-ABL+CML细胞株,通过逐步递增Ponatinib浓度的方法建立耐药细胞株模型。以敏感细胞株为对照,PCR测序未发现其BCR-ABL激酶结构域存在点突变。用伊马替尼,尼洛替尼和达沙替尼分别处理耐药及敏感细胞株,MTS实验检测细胞增殖活性证实Ponatinib耐药的32D (BCR-ABL) ponR和K562ponR细胞,同时也存在对伊马替尼,尼洛替尼和达沙替尼耐药。Westem blot检测发现较低浓度Poantinib即可抑制耐药细胞磷酸化BCR-ABL蛋白表达。以上结果均提示耐药细胞呈现出一种非BCR-ABL酪氨酸激酶依赖的耐药分子机制。
对32D (BCR-ABL) ponR细胞进一步研究发现,在BCR-ABL活性受到抑制时,其下游底物STAT5仍保持活性。以小分子抑制剂为基础的合成性致死筛选试验结果显示只有某些JAK家族的抑制剂协同Ponatinib才会对32D (BCR-ABL) ponR耐药细胞产生合成性致死作用。shRNA敲除32D (BCR-ABL) ponR耐药细胞BCR-ABL基因模拟Ponatinib药理作用,MTS实验显示,单一JAK家族的抑制剂即可抑制耐药细胞的增殖,说明该细胞耐药与活化的JAK/STAT辅助信号转导通路有关。基因芯片技术分析耐药及敏感细胞基因表达情况,并用实时荧光定量PCR对其进行验证,发现耐药细胞中细胞因子IL-3表达明显上调(P<0.01),且IL-3中和抗体可以减弱耐药细胞对Ponatinib的耐受。而K562ponR细胞也同样存在着辅助信号转导通路MEK/ERK的活化,联合使用Ponatinib和MEK/ERK抑制剂可以抑制K562ponR细胞的生长。
我们也分析了1例经Ponatinib治疗失败的患者标本,该患者存在BCR-ABLT315I突变,但BCR-ABLT315I活性在体外可被低浓度Ponatinib抑制,合成性致死筛选试验siRNA实验发现,敲除CSF1R可协同Ponatinib显著降低白血病细胞的生长,提示其可能是通过激活CSF1R辅助信号转导通路产生的耐药。
通过这些研究说明Ponatinib耐药呈现一种非BCR-ABL依赖的耐药分子机制,针对这类患者同时采取抑制BCR-ABL及辅助信号通路抑制剂可以达到理想的治疗效果。
Chronic myeloid leukemia (CML) arises from the neoplastic transformation of a hematopoietic stem cell, which is characterized by the Philadelphia chromosome. A P210BCR-ABL protein is generated by the BCR-ABL fusion gene, which is a constitutively active tyrosine kinase that drives cell proliferation and apoptosis through multiple downstream signal pathways. Since the BCR-ABL is considered essential for the disease progression, targeting the tyrosine kinase activity of BCR-ABL shows an attractive therapeutic strategy. The BCR-ABL kinase inhibitor imatinib, because of the safety and effectivity, has become the first line therapy of CML. But still some patients show primary or acquired resistant to imatinib therapy, the most frequently described mechanism of acquired resistance to imatinb is the occurrence of point mutations in the kinase domain of BCR-ABL. Patients who are intolerant or resistant to imatinib have the effective salvage therapy of the second line ABL kinase inhibitors nilotinib and dasatinib. Both of them target most mutants except the cross resistant BCR-ABLY3151mutation.
Ponatinib, from the Ariad pharmacy company, is a multitargeted kinase inhibitor that can even inhibit BCR-ABLT3151, which is the third line therapy for patients with CML. BCR-ABL kinase domain mutation-mediated ponatinib resistance has been investigated in vitro. A pivotal phase II trial is underway, almost94%CML patients have previously failed at least2tyrosine kinase inhibitors, after ponatinib treatment half of the patients achieved major cytogenetic response, but there are still some patients resistant to ponatinib therapy.
Here, we developed ponatinib resistant, BCR-ABL positive cell lines lacking a kinase domain mutation and investigated mechanisms of resistance, trying to possibly in advance of full mechanistic understanding in the clinic, to search and investigate new tyrosine kinase inhibitor, and to restore ponatinib resistant paitent's response.
Two BCR-ABL+cell lines,32D(BCR-ABL) and K562, were exposed to escalating concentrations of ponatinib to generate ponatinib-resistant cells. BCR-ABL kinase domain sequencing of resistant cells confirmed BCR-ABL to be unmutated. MTS cell proliferation assay of sensitive and resistant cells showed that ponatinib resistant cell also exhibited resistance to imatinib, nilotinib and dasatinib. In each of the ponatinib-resistant cell lines, BCR-ABL tyrosine kinase activity was pharmacologically silenced by low concentrations of ponatinib and yet the cells survived. All data indicated a BCR-ABL kinase independent mechanism of resistance.
Based on western blot, tyrosine phosphorylation of the BCR-ABL downstream target STAT5was substantially maintained despite ponatinib-mediated inhibition of BCR-ABL1catalytic activity in32D (BCR-ABL)ponR cells. A small molecule inhibitors screen was applied to the32D(BCR-ABL)ponR resistant cell in the presence or absence of ponatinib to assess synthetic lethality. Only dual combinations of ponatinib and certain JAK inhibitors are lethal to resistant cell. Knocking down the BCR-ABL by shRNA mimicked the ponatinib effect, resistant cell exhibited single agent sensitivity to some JAK inhibitors, which suggested that JAK/STAT co-critical signaling pathway may be involved in this BCR-ABL independent mechanism of resistance. Sensitive and resistant cells were used for gene microarray analysis, and validated by the real time PCR. IL-3expression is up-regulated in resistant cell (p<0.01), and the IL-3neutralizing antibody could reduce the tolerance of resistant cell to ponatinib. Synthetic lethality screening identified MEK/ERK co-critical signaling pathway in K562ponR cells, only ponatinib synergizes with MEK/ERK inhibition to induce synthetic lethality in ponatinib resistant K562ponR cells.
We analyzed one ponatinib treatment failure patient sample recently, only BCR-ABLT3151mutation was found in this patient and BCR-ABLT3151activity was inhibited ex vivo by low concentration of ponatinib. Synthetic lethality siRNA screening showed that combination of ponatinib and knockdown CSFlR drastically reduces CML cell viability, which suggested that CSFlR co-critical signaling pathway was involved in this BCR-ABL independent mechanism of resistance.
Our findings indicate a BCR-ABL independent mechanism of ponatinib resistance, some relapsed CML patients may benefit from targeting both BCR-ABL and co-critical signaling pathways.
引文
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