The Impact of SETD2 on Tumor Microenvironment in Clear Cell RCC

Scott Haake, MD

The SET domain-containing protein 2 (SETD2) is common in clear cell renal cell carcinoma (RCC), occurring in about 10% to 15% of patients, and is known to play a role in the tumor microenvironment. However, investigators lack literature on the biology of the SETD2 mutation and how it could play a role in tumor growth.

At the 2019 International Kidney Cancer Symposium (IKCS), a study analyzed novel SETD2-dependent changes to the cellular lysine methylation landscape in the kidney cancer setting. The hypothesis was that SETD2-mutant tumors will have an increased sensitivity to therapies that target protein translation. Investigators utilized an agnostic approach with a mass spectrometry-based technique to evaluate these changes.

Overall, investigators observed a decrease in protein translations, which may represent a new therapeutic vulnerability of these cells that can be exploited with targeted therapies.

“The key takeaway is that tumor genomics matter, and they drive biology,” said Scott Haake, MD, following his presentation at the 2019 IKCS. “If we can exploit that biology to apply targeted therapies, this is an opportunity for new therapeutic maneuvers that are tailored to the patients and individual tumors.”

In an interview with Targeted Oncology, Haake, professor of Medicine, Vanderbilt University School of Medicine, discussed the current understandings of SETD2 mutations in clear cell RCC and the findings presented at the 2019 IKCS.

TARGETED ONCOLOGY: What do we know thus far about how SETD2 influences the tumor microenvironment?

Haake: SETD2 is mutated in 10% to 15% of clear cell RCC. Its role in the tumor microenvironment specifically is probably less well understood. However, it is thought to be a critical driver of tumor growth and progression as loss of SETD2 function is thought to increase as tumors metastasize.

TARGETED ONCOLOGY: Could you explain the biology of SETD?

Haake: It’s less well understood than we would like to acknowledge. Classically SETD2 modulates the epigenetics of the cell or chromatin structure, which is the way that the DNA is packaged into the cell, and when you lose SETD2, it changes that structure in a way that is thought to influence gene expression. This is classically how we think about SETD2 biology. More recently, there has been data showing that SETD2 has many other functions, including modulating tubulin structure which is important in mitosis and chromosome segregation, as well as inflammatory signaling through STAT1.

Because we still have an incomplete picture of how SETD2 is important for tumor development, this was 1 of the impotencies for the current study where we took an agnostic approach to see the different ways thatSETD2 can modulate cell function in the context of cancer.

[To identify SEDT2 mutations], stereotypical next-generation sequencing approaches are the way of the future, and that is what everyone does.

TARGETED ONCOLOGY: Are there any other therapies for targeting the SETD2 mutation?

Haake: Through our work, we have identified a novel role of SETD2 regulating protein translation. I have mentioned the classic ways that SETD2 influences cell biology, but our work suggests that in addition, SETD2is regulating protein translation at the ribosome by regulating methylation of certain translation elongation factors. In SETD2-mutant tumors, you lose methylation of these elongation factors, which decreases protein translation, so we think this might be an opportunity for synthetic lethality in SETD2-mutant tumors where these cells will have increased sensitivity to therapies that target protein translation, or at least that is the hypothesis we are pursuing.

TARGETED ONCOLOGY: Could you provide an overview of your presentation on SETD2 from the 2019 IKCS?

Haake: There are a number of targets for SETD2 that have been described in the literature, but we wanted to take a more agnostic approach. We used a mass spectrometry-based technique to look at SETD2-dependent changes in lysine methylation in proximal renal tubular cells, which are the cells from which RCC is thought to derive.

One of the things we observed was the loss of methylation in a number of distinct lysine residues within an elongation factor called EF1A. It has been shown in lung cancer that loss of methylation of these lysine residues in EF1A correlates with decreased protein translation and decreased progression of tumors. Sure enough, when we look at this in our kidney cancer cells, we see decreased protein translation, and when we look at tumors from humans with SETD2 mutations, we also observed similar changes. We think this is a new aspect of SETD2 biology in the context of kidney cancer and may represent a therapeutic vulnerability of these cells, which we can exploit.

TARGETED ONCOLOGY: What are the next steps for this research?

Haake: That is really where we are at now. We are doing a handful of experiments to validate the mechanism I proposed, but we are also testing drugs and wild-type, as well as SETD2-knockout cells which target protein translation to test this hypothesis that SETD2-knockout cells are going to have increased sensitivity to these sorts of drugs.

TARGETED ONCOLOGY: What is the key takeaway from your presentation?

Haake: The key takeaway is that tumor genomics matter, and they drive biology. If we can exploit that biology to apply targeted therapies, this is an opportunity for new therapeutic maneuvers that are tailored to the patients and individual tumors.