Unlike with some other solid tumors, there are not many targetable mutations found in renal cell carcinoma (RCC).
“Having biomarkers for prognosis is important, but at the end of the day patients and physicians want to know what we can do differently as a result of that biomarker,” explained Bradley McGregor, MD, clinical director of the Lank Center of Genitourinary Oncology at the Dana-Farber Cancer Institute in Boston, Massachusetts. “The first step to finding those opportunities for treatment is, however, findings these types of biomarkers.”
One study recently found that upregulation of cytoskeleton-associated protein 4 (CKAP4) was associated with worsened characteristics of clear cell RCC.1 A knowledge-based search for genes altered at a lower frequency in a cohort of patients with clear cell RCC in The Cancer Genome Atlas dataset revealed that CKAP4 was overexpressed in about 5% of cases.
The authors conducted an in silico exploratory analysis and found that overexpressed CKAP4 was significantly associated with tumor, nodal, and metastasis stages, as well as Fuhrman grades. A further validation analysis in 124 patient tumor samples confirmed this finding, and also found that CKAP4 overexpression was associated with patient age and status of neoadjuvant therapy.
“Overexpressed CKAP4, though only in 5% of cases, was significantly associated worsened prognosis and shorter disease-free period,” the authors wrote. “In particular, patients with CKAP4 overexpression showed a drastic fall of overall survival, indicating a strong pro-tumorigenic role.”
A pathway analysis showed significant cell cycle progression at G2/M phase, and that expression of CCNB1 and CCNB2 was correlated with CKAP4 expression. The researchers found that CKAP4 silencing significantly inhibited cell proliferation, invasion, and migration of clear cell RCC cells, and upregulation significantly promoted these functions.
The researchers used a CDK/CCNB inhibitor (RO-3306) and found that it significantly inhibited “anchorage-independent growth in terms of colony formation” and in vivo tumor growth of clear cell RCC cells that overexpressed CKAP4.
According to Dr McGregor, these results are too early to have any clinical implications for patients with RCC and are unlikely to change treatment for patients in the short term.
“Similarly, while we know that VHL is a driving mutation of RCC, we give the same first-line therapies regardless of its presence,” Dr McGregor said. “We do not have targeted therapies that correlate with certain mutations in RCC though this continues to evolve.”
Currently, the only way most patients with RCC would be screened for a mutation like CKAP4 would be through early clinical trials. Whether this marker will become targetable in the clinic is yet to be seen.
- Sun C, Geng J, Yan Y, et al. Overexpression of CKAP4 is associated with poor prognosis in clear cell renal cell carcinoma and functions via cyclin B signaling. J Cancer. 2017;8(19):4018-26. doi: 10.7150/jca.21226