Structural basis of acquired resistance to selpercatinib and pralsetinib mediated by non-gatekeeper RET mutations.
Structural basis of acquired resistance to selpercatinib and pralsetinib mediated by non-gatekeeper RET mutations.
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非看门人RET突变介导的selpercatinib和pralsetinib获得性耐药的结构基础。
DOI：
10.1016/j.annonc.2020.10.599
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发表时间：
2021-03
期刊：
影响因子：
--
通讯作者：
Wu J
中科院分区：
文献类型：
--
作者：
Subbiah V;Shen T;Terzyan SS;Liu X;Hu X;Patel KP;Hu M;Cabanillas M;Behrang A;Meric-Bernstam F;Vo PTT;Mooers BHM;Wu J
Selpercatinib （LOXO-292）和pralsetinib （BLU-667）是治疗晚期ret改变的甲状腺癌和非小细胞肺癌（NSCLC）的高效ret选择性蛋白酪氨酸激酶抑制剂（TKIs）。分析RET突变体对这些药物的耐药性并揭示分子基础对于改善患者预后至关重要。我们分析了一名ret突变型甲状腺髓样癌（MTC）患者和一名CCDC6-RET融合的NSCLC患者的游离dna (cfdna)，这两名患者对selpercatinib有显著反应，后来出现耐药性。在细胞培养中鉴定出selpercatinib抗性RET突变体并与普拉塞替尼交叉分析。利用同步辐射采集的高分辨率衍射数据，确定了RET-selpercatinib和RET-pralsetinib配合物的晶体结构。在一名患有RETM918T/V804M/L的MTC患者的cfdna中发现了溶剂前部的RETG810C/S突变和铰链区域的RETY806C/N突变，该患者最初对selpercatinib有反应并产生耐药性。RETG810C突变体在一名对自帕替尼产生获得性耐药的ccdc6 - ret融合NSCLC患者的cfdna中被检测到。从39个selpercatinib耐药细胞系中鉴定出3个非守门人残基的5个RET激酶结构域突变。所有5个自泊卡替尼耐药RET突变体均对普拉塞替尼交叉耐药。RET-selpercatinib和RET-pralsetinib复合物的x射线晶体结构显示，与其他tki复合物不同，这两种RET tki复合物的一端锚定在前间隙，并环绕门壁进入后间隙。在溶剂前部和铰链处的RET突变对这两种药物都有耐药性。Selpercatinib和pralsetinib使用非常规模式结合RET，避免了来自守门人突变的干扰，但易受非守门人突变的影响。
Selpercatinib (LOXO-292) and pralsetinib (BLU-667) are highly potent RET-selective protein tyrosine kinase inhibitors (TKIs) for treating advanced RET-altered thyroid cancers and non-small-cell lung cancer (NSCLC). It is critical to analyze RET mutants resistant to these drugs and unravel the molecular basis to improve patient outcomes. Cell-free DNAs (cfDNAs) were analyzed in a RET-mutant medullary thyroid cancer (MTC) patient and a CCDC6-RET fusion NSCLC patient who had dramatic response to selpercatinib and later developed resistance. Selpercatinib-resistant RET mutants were identified and cross-profiled with pralsetinib in cell cultures. Crystal structures of RET-selpercatinib and RET-pralsetinib complexes were determined based on high-resolution diffraction data collected with synchrotron radiation. RETG810C/S mutations at the solvent front and RETY806C/N mutation at the hinge region were found in cfDNAs of an MTC patient with RETM918T/V804M/L, who initially responded to selpercatinib and developed resistance. RETG810C mutant was detected in cfDNAs of a CCDC6-RET-fusion NSCLC patient who developed acquired resistance to selpercatinib. Five RET kinase domain mutations at three non-gatekeeper residues were identified from 39 selpercatinib-resistant cell lines. All five selpercatinib-resistant RET mutants were cross-resistant to pralsetinib. X-ray crystal structures of the RET-selpercatinib and RET-pralsetinib complexes reveal that, unlike other TKIs, these two RET TKIs anchor one end in the front cleft and wrap around the gate wall to access the back cleft. RET mutations at the solvent front and the hinge are resistant to both drugs. Selpercatinib and pralsetinib use an unconventional mode to bind RET that avoids the interference from gatekeeper mutations but is vulnerable to non-gatekeeper mutations.
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影响因子：
7.3
作者：
Liu, Xuan;Shen, Tao;Wu, Jie
通讯作者：
Wu, Jie
DOI：
10.1056/nejmoa2005653
发表时间：
2020-08-27
期刊：
The New England journal of medicine
影响因子：
--
作者：
Drilon A;Oxnard GR;Tan DSW;Loong HHF;Johnson M;Gainor J;McCoach CE;Gautschi O;Besse B;Cho BC;Peled N;Weiss J;Kim YJ;Ohe Y;Nishio M;Park K;Patel J;Seto T;Sakamoto T;Rosen E;Shah MH;Barlesi F;Cassier PA;Bazhenova L;De Braud F;Garralda E;Velcheti V;Satouchi M;Ohashi K;Pennell NA;Reckamp KL;Dy GK;Wolf J;Solomon B;Falchook G;Ebata K;Nguyen M;Nair B;Zhu EY;Yang L;Huang X;Olek E;Rothenberg SM;Goto K;Subbiah V
通讯作者：
Subbiah V
影响因子：
16.6
作者：
Nakaoku T;Kohno T;Araki M;Niho S;Chauhan R;Knowles PP;Tsuchihara K;Matsumoto S;Shimada Y;Mimaki S;Ishii G;Ichikawa H;Nagatoishi S;Tsumoto K;Okuno Y;Yoh K;McDonald NQ;Goto K
通讯作者：
Goto K
影响因子：
28.2
作者：
Friboulet L;Li N;Katayama R;Lee CC;Gainor JF;Crystal AS;Michellys PY;Awad MM;Yanagitani N;Kim S;Pferdekamper AC;Li J;Kasibhatla S;Sun F;Sun X;Hua S;McNamara P;Mahmood S;Lockerman EL;Fujita N;Nishio M;Harris JL;Shaw AT;Engelman JA
通讯作者：
Engelman JA
影响因子：
14.9
作者：
wwPDB consortium
通讯作者：
wwPDB consortium