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Molecular Therapeutic Advances in Personalized Therapy of Melanoma and Non-Small Cell Lung Cancer

机译：黑色素瘤和非小细胞肺癌个性化治疗的分子治疗进展

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The incorporation of individualized molecular therapeutics into routine clinical practice for both non-small cell lung cancer (NSCLC) and melanoma are amongst the most significant advances of the last decades in medical oncology. In NSCLC activating somatic mutations in exons encoding the tyrosine kinase domain of the Epidermal Growth Factor Receptor (EGFR) gene have been found to be predictive of a response to treatment with tyrosine kinase inhibitors (TKI), erlotinib or gefitinib. More recently the EML4-ALK fusion gene which occurs in 3–5% of NSCLC has been found to predict sensitivity to crizotinib an inhibitor of the anaplastic lymphoma kinase (ALK) receptor tyrosine kinase. Similarly in melanoma, 50% of cases have BRAF mutations in exon 15 mostly V600E and these cases are sensitive to the BRAF inhibitors vemurafenib or dabrafenib. In a Phase III study of advanced melanoma cases with this mutation vemurafenib improved survival from 64% to 84% at 6 months, when compared with dacarbazine. In both NSCLC and melanoma clinical benefit is not obtained in patients without these genomic changes, and moreover in the case of vemurafenib the therapy may theoretically induce proliferation of cases of melanoma without BRAF mutations. An emerging clinical challenge is that of acquired resistance after initial responses to targeted therapeutics. Resistance to the TKI’s in NSCLC is most frequently due to acquisition of secondary mutations within the tyrosine kinase of the EGFR or alternatively activation of alternative tyrosine kinases such as C-MET. Mechanisms of drug resistance in melanoma to vemurafenib do not involve mutations in BRAF itself but are associated with a variety of molecular changes including RAF1 or COT gene over expression, activating mutations in RAS or increased activation of the receptor tyrosine kinase PDGFRβ. Importantly these data support introducing re-biopsy of tumors at progression to continue to personalize the choice of therapy throughout the patient’s disease course.
机译：在过去的几十年中，医学肿瘤学领域最重要的进展之一就是将个体化的分子疗法纳入非小细胞肺癌（NSCLC）和黑色素瘤的常规临床实践中。在NSCLC中，已发现编码表皮生长因子受体（EGFR）基因酪氨酸激酶结构域的外显子中的体细胞突变可预测酪氨酸激酶抑制剂（TKI），厄洛替尼或吉非替尼对治疗的反应。最近发现，在NSCLC的3-5％中出现的EML4-ALK融合基因可预测对间断性淋巴瘤激酶（ALK）受体酪氨酸激酶抑制剂克唑替尼的敏感性。类似地，在黑色素瘤中，50％的病例在15号外显子（主要是V600E）中有BRAF突变，这些病例对BRAF抑制剂vemurafenib或dabrafenib敏感。与达卡巴嗪相比，维拉非尼在具有这种突变的晚期黑色素瘤病例的III期研究中将6个月生存率从64％提高到84％。在没有这些基因组改变的患者中，在NSCLC和黑色素瘤中均未获得临床益处，此外，在维罗非尼的情况下，该疗法理论上可诱导无BRAF突变的黑色素瘤病例的增殖。新兴的临床挑战是​​对靶向治疗剂的初始反应后获得的耐药性。 NSCLC中对TKI的耐药性最常见的原因是在EGFR酪氨酸激酶内获得了继发性突变，或激活了其他酪氨酸激酶（例如C-MET）。黑色素瘤对维罗非尼的耐药机制并不涉及BRAF本身的突变，而是与包括RAF1或COT基因过度表达，RAS中的激活突变或受体酪氨酸激酶PDGFRβ的激活增加在内的多种分子变化有关。重要的是，这些数据支持在病程进展中进行肿瘤再活检，从而在患者的整个病程中继续个性化治疗选择。

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