BACKGROUND Gain-of-function mutations in KIT are driver events of oncogenesis in mast cell tumours (MCTs) affecting companion animals. Somatic mutations of KIT determine the constitutive activation of the tyrosine kinase receptor leading to a worse prognosis and a shorter survival time than MCTs harbouring wild-type KIT. However, canine MCTs carrying KIT somatic mutations generally respond well to tyrosine kinase inhibitors; hence their presence represents a predictor of treatment effectiveness, and its detection allows implementing a stratified medical approach. Despite this, veterinary oncologists experience treatment failures, even with targeted therapies whose cause cannot be elucidated. The first case of an MCT-affected dog caused by a secondary mutation in the tyrosine kinase domain responsible for resistance has recently been reported. The knowledge of this and all the other mutations responsible for resistance would allow the effective bedside implementation of a deeply stratified and more effective medical approach. CASE PRESENTATION The second case of a canine MCT carrying a different resistance mutation is herein described. The case was characterised by aggressive behaviour and early metastasis unresponsive to both vinblastine- and masitinib-based treatments. Molecular profiling of the tumoural masses revealed two different mutations; other than the already known activating mutation p.Asn508Ile in KIT exon 9, which is tyrosine kinase inhibitor-sensitive, a nearly adjacent secondary missense mutation, p.Ala510Val, which had never before been described, was detected. In vitro transfection experiments showed that the secondary mutation did not cause the constitutive activation by itself but played a role in conferring resistance to masitinib. CONCLUSIONS This study highlighted the importance of the accurate molecular profiling of an MCT in order to improve understanding of the molecular mechanism underlying tumourigenesis and reveal chemoresistance in MCTs for more effective therapies. The detection of the somatic mutations responsible for resistance should be included in the molecular screening of MCTs, and a systematic analysis of all the cases characterised by unexpected refractoriness to therapies should be investigated in depth at both the genetic and the phenotypic level.

中文翻译：

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携带激活突变p.Asn508Ile的皮肤肥大细胞肿瘤中的继发性KIT突变p.Ala510Val赋予狗对马赛替尼的抗性。

背景技术KIT中的功能获得性突变是肥大细胞瘤（MCT）中影响伴侣动物的肿瘤发生的驱动器事件。与携带野生型KIT的MCT相比，KIT的体细胞突变决定了酪氨酸激酶受体的组成性激活，从而导致更差的预后和更短的生存时间。但是，携带KIT体细胞突变的犬MCT通常对酪氨酸激酶抑制剂反应良好。因此，它们的存在代表治疗效果的预测指标，并且其检测可以实施分层的医学方法。尽管如此，即使采用无法阐明病因的靶向疗法，兽医肿瘤学家仍会遇到治疗失败的情况。最近已经报道了第一例由负责抵抗的酪氨酸激酶结构域的二次突变引起的受MCT感染的狗。对此和引起耐药性的所有其他突变的知识将允许在床旁有效实施深度分层且更有效的医学方法。病例表达本文描述了携带不同抗性突变的犬MCT的第二种情况。该病例的特征是攻击性行为和对基于长春碱和马赛替尼的治疗均无反应的早期转移。肿瘤肿块的分子图谱显示两个不同的突变。除了对酪氨酸激酶抑制剂敏感的KIT外显子9中已知的激活突变p.Asn508Ile之外，还检测到了几乎相邻的继发性错义突变p.Ala510Val，这是以前从未描述过的。体外转染实验表明，二级突变本身不会引起组成性激活，但在赋予对马赛替尼的抗性中起作用。结论这项研究强调了MCT准确分子谱分析的重要性，以增进对肿瘤发生的分子机制的了解，并揭示MCT中的化学抗药性，以便进行更有效的治疗。在MCT的分子筛查中应包括对引起耐药性的体细胞突变的检测，并且应在遗传和表型水平上深入研究对所有以治疗为意外难治性特征的病例进行系统分析。结论这项研究强调了MCT准确分子谱分析的重要性，以增进对肿瘤发生的分子机制的了解，并揭示MCT中的化学抗药性，以便进行更有效的治疗。在MCT的分子筛查中应包括对引起耐药性的体细胞突变的检测，并且应在遗传和表型水平上深入研究对所有以治疗为意外难治性特征的病例进行系统分析。结论这项研究强调了MCT准确分子谱分析的重要性，以增进对肿瘤发生的分子机制的了解，并揭示MCT中的化学抗药性，以便进行更有效的治疗。在MCT的分子筛查中应包括对引起耐药性的体细胞突变的检测，并且应在遗传和表型水平上深入研究对所有以治疗的意外难治性为特征的病例的系统分析。