Understanding the Role of MET Kinase in Cancer Therapy

In the article that accompanies this editorial, Choueiri et al present an important study investigating the role of foretinib in the treatment of papillary renal cell carcinomas (PRC). PRC is the most common form of nonclear renal cell carcinoma (RCC). Given the relative rarity of this subtype of RCC, only a limited amount of information exists to guide treatment decisions. In addition to unique histologic features that distinguish PRC from clear-cell RCC, there are unique molecular features associated with the disease. In particular, there is overexpression and overactivation of the MET kinase through a variety of means, including mutation and copy number aberration. Although the presented study failed to demonstrate activity as defined by the primary end point of overall response rate, the investigators do show potent clinical activity in this small sample set that justifies additional work in this area. In comparison to currently used agents targeting the vascular endothelial growth factor receptors (VEGFRs) or the mammalian target of rapamycin (mTOR), foretinib appears to be more clinically active. Whereas this agent does inhibit a number of non-VEGFR, non-MET tyrosine kinases, particular emphasis in this study is placed on MET given the body of knowledge of MET variation in PRC. The development of targeted therapeutics in cancer has not yet met the high expectations of patients and physicians. The majority of this disappointment appears to result from the rather limited rationale for advancement of certain agents in particular disease systems or an inappropriate understanding of the biology of the system. The clinical studies performed often fail to answer an important question: is the relevant molecular target present in patients, and does this correlate with disease biology or response to therapy? Choueiri et al are to be congratulated for taking their observation beyond a generalization about PRC and aberration of MET expression or function. Rather than assuming that any variation in MET signaling is equivalent, the investigators stratified patients by the type of MET abnormality present in the pool of responders. In addition to duplication of chromosome 7 and other copy number aberrations, there are more than 60 cataloged mutations in the MET gene. A proportion of patients have these mutations in MET in the germline, whereas other may acquire MET mutation through a variety of means. This study points toward the importance of MET aberration in the germline DNA. Interest in MET as a target of anticancer therapy has grown. In particular there are several groups that have proposed that activation of MET may be an adaptive response to certain forms of anticancer therapy. In particular, the MET–epidermal growth factor receptor (EGFR) interaction has been pursued as a means of overcoming EGFR therapy resistance. Currently, there is growing interest in the activity of MET and VEGF as cooperative signals in tumor invasion and angiogenesis. These types of cooperative signaling interaction may account for some of the biologic activity seen with other multitargeted tyrosine kinase inhibitors such as cabozantinib, which has shown activity in castration-resistant prostate cancer, medullary thyroid cancer, hepatocellular carcinoma, and other settings. These findings bear high value if MET functions primarily as a somatic “adaptive” response to external pressure. The MET-VEGFR interaction in the tumor microenvironment bears particular interest given the high rate of pulmonary emboli in this study, perhaps implying a greater degree of vascular disruption. Interestingly, the investigators in this study note that germline mutation bears stronger predictive value than somatic mutation. This finding has both clinical and scientific import. First, although studies restricted to germline MET mutation may potentially strongly validate the importance of this observation, they would limit the scope of clinical benefit severely without taking advantage of the observation that patients without germline mutations did experience benefit from therapy, although to a lesser degree. Second, the importance of germline mutation (as compared with somatic mutation) must be considered and may have importance in understanding the function of these genetic aberrations. This may lead to important insights that may guide therapeutic development. In this study, classification of patients was restricted only to genetic information about MET, which may not fully reflect the activity of this pathway in patients especially given findings that gene expression and protein expression levels do not strongly correlate with MET. However, given the limited tools for detecting the presence of MET in tissue and the lack of consensus on reliable means of defining its activation state, the genetic approach is to be considered the most feasible to use at this time. As presented, the study introduces a number of important clinical and translational questions that will advance the field of therapeutics in the clinical entity of PRC, but also in turn will enhance the field of rational therapeutics and personalized medicine. First, although germline mutation predicted higher rates of response, half the patients with germline mutation still did not experience benefit, and the reasons for this are poorly understood. Second, do these findings suggest JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 31 NUMBER 2 JANUARY 1