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Selectively targeting inosine monophosphate dehydrogenase-2 impairs brain metastatic potential while preserving
Agata M Kieliszek1,2,3, Erika Apel1,4, Suky Zheng1,2,4
1Centre for Discovery and Cancer Research, Faculty of Health Sciences, McMaster University, Hamilton, ON L8S 4L8, Canada.
Abstract:
Brain metastases (BM) occur in 26% of cancer patients and have a 90% mortality rate within 1 y of diagnosis, yet the current standard of care remains palliative. We have previously shown that de novo GTP synthesis is a druggable metabolic vulnerability in BM cells, through its rate-limiting enzyme, inosine monophosphate dehydrogenase (IMPDH). IMPDH inhibitors have progressed to phase-II oncology trials in the past, failing largely due to dose-limiting toxicities associated with off-target inhibition of IMPDH1, the constitutively expressed isoenzyme in normal human lymphocytes. Here, we determined that a single subtype (isoenzyme) of IMPDH, IMPDH2, is specifically upregulated in brain metastasis-initiating cells (BMICs), absent in normal brain tissue, and is sufficient to drive the formation of BM. Moreover, we show that genetic knockout of IMPDH2 stops the proliferation of BM cells in vitro and the onset of BM in vivo. We synthesized IMPDH2-selective compounds and showed that they maintain a potent antiproliferation effect on BMICs, but spare immune cell function compared to previously developed pan-IMPDH inhibitors. Furthermore, we introduce a positive correlation between compound selectivity for IMPDH2 and the ability to synergize with Osimertinib: the standard of care for EGFR-mutant non-small cell lung cancer. Overall, our results suggest that specifically blocking IMPDH2 is an effective therapeutic strategy for BM by overcoming the immune suppressive effects that have hindered the clinical development of pan-IMPDH inhibitors in the past. An IMPDH2 specific therapy could be coadministered with primary tumor standard of care treatments to provide a safe and interceptional approach for BM.
Insights
Targeting IMPDH2, a specific enzyme in brain metastasis-initiating cells, offers a new therapeutic strategy. This approach overcomes toxicity issues of older drugs, potentially improving brain metastasis treatment.
Area of Science:
- Oncology
- Metabolic Pathways
- Cancer Metastasis
Background:
- Brain metastases (BM) are a significant cause of cancer mortality with limited treatment options.
- Previous attempts to target GTP synthesis via IMPDH inhibitors were hindered by toxicity.
- A specific vulnerability in BM cells involves de novo GTP synthesis regulated by IMPDH.
Purpose of the Study:
- To identify a specific target for treating brain metastases.
- To develop a safer therapeutic strategy by overcoming off-target toxicities.
- To evaluate the efficacy of targeting IMPDH2 in brain metastasis.
Main Methods:
- Investigated IMPDH isoenzyme expression in brain metastasis-initiating cells (BMICs).
- Utilized genetic knockout of IMPDH2 to assess its role in BM cell proliferation and formation.
- Synthesized and tested IMPDH2-selective compounds for anti-proliferative effects and immune sparing.
- Assessed synergy between IMPDH2 inhibitors and Osimertinib.
Main Results:
- IMPDH2 is specifically upregulated in BMICs and drives brain metastasis formation.
- Genetic deletion of IMPDH2 inhibited BM cell proliferation in vitro and BM onset in vivo.
- IMPDH2-selective compounds showed potent anti-proliferative effects on BMICs with preserved immune function.
- Compound selectivity for IMPDH2 correlated positively with synergy with Osimertinib.
Conclusions:
- Targeting IMPDH2 represents a promising therapeutic strategy for brain metastases.
- Selective IMPDH2 inhibition overcomes the immune-related toxicities of pan-IMPDH inhibitors.
- IMPDH2 inhibitors offer a safe, co-administered approach to intercept brain metastasis.
