Further Advances in Genetically Informed Lung Cancer Medicine

作者: Caroline Nebhan , William Pao

DOI: 10.1097/JTO.0B013E31828F583C

关键词:

摘要: During the past decade, treatment of patients with metastatic non-small cell lung cancer (NSCLC) has undergone a major paradigm shift. In early 2000s, such were treated empirically chemotherapy. Today, we know that NSCLC is comprised multiple clinically relevant molecular subsets defined by specific ‘driver mutations’. Such mutations result in constitutively active mutant signaling proteins and uncontrolled cellular proliferation. Remarkably, many these are targetable kinase inhibitors, can be more effective than The list ‘actionable’ targets growing quickly currently includes at least EGFR L858R substitutions exon 19 deletion mutants,1 ALK fusions,2 ROS1 fusions,3 MET amplification,4 BRAF V600E substitutions.5 mutants targeted inhibitors gefitinib or erlotinib, ALK/ROS1/MET aberrations crizotinib, vemurafenib, respectively. this issue Journal Thoracic Oncology, 2 case reports further extend paradigm: first involves new target, RET fusions, second demonstrates mechanisms sensitivity resistance to another selective inhibitor cancer. Activating fusions involving receptor tyrosine reported adenocarcinoma 2012.6, 7, 8, 9 (rearranged during transfection) was originally discovered as proto-oncogene 1985.10 Subsequently, found papillary medullary thyroid carcinomas, occurring both hereditary sporadic tumors.11, 12 Some cancers (PTCs) harbor higher prevalence history radiation exposure young adults pediatric populations.13 Activating translocations have also been chronic myelomonocytic leukemia (CMML).14 In cancer, detected collectively about 1% NSCLCs.6, 15 5’-fusion partners include NCOA4, CCDC6 KIF5B. Clinical characteristics associated never smoking status, histology, younger age diagnosis. Importantly, rarely if ever tumors other drivers, i.e. EGFR, KRAS, HER2, ALK.8 Preclinical studies suggested harboring should sensitive inhibition TKIs. For example, human line LC-2/ad CCDC6-RET fusion showed distinctive inhibitor, vandetanib, but not gefitinib, among 39 lines tested.16 Vandetanib inhibits while only. Other engineered models show may ‘off-target’ activity, sunitinib, sorafenib, motesanib, cabozantinib.17 humans, one patient fusion-positive CMML had documented cytological clinical remission on sorafenib.14 In Gautschi et al. report our knowledge known RET-fusion positive respond RET-targeted therapy. This patient, who received tumor for KIF5B-RET negative drivers including BRAF, ROS1, amplification. Decrease size observed after week vandetanib treatment; imaging four weeks confirmed response. Treatment well-tolerated patient. A familiar challenge therapies acquired resistance. Mechanisms well-characterized tumors.18 A common mechanism development second-site mutations. RET, vitro analyses already identified codons 804 806 mediators resistance.19,20 future studies, it will important establish whether TKIs. Although findings from only single identification response upon suggests indeed represent actionable driver mutation cancer. screened adenocarcinoma, especially lack Outstanding questions include: what rate overall survival cohort prospectively vandetanib? Is ‘best’ TKI treatment? Will there enough perform randomized trial between chemotherapy determine which superior? And how overcome? As answers unfold, speed observations now translated lab (RET published February 2012) clinic (a responds 2013) provide inspiration hope expanding era molecularly-targeted therapeutics. Also Rudin novel course 63yo smoker BRAFV600E-mutant whose disease responded then progressed dabrafenib, inhibitor. ~2% adenocarcinomas,21 50% melanomas. latter disease, dabrafenib shown superior conventional chemotherapy.22 Potential melanoma secondary NRAS, encodes GTPase, MEK1, serine-threonine kinase, downstream RAF-RAS-MEK-ERK cascade.23 case, analysis tissue obtained progression revealed KRAS G12D present pre-treatment biopsy. Like GTPase same gene family. NRAS rare relatively frequent.24 Given similarities probably mediated patient. Importantly, finding possible due acquisition serial biopsies. While no agents yet treat effectively tumors, highlights importance repeat mutational profiling understand inevitably evolve agents.

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