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Two studies show MTH1 offers promising new target for cancer treatment

2 Apr 2014

by ecancer reporter Janet Fricker

A new approach to cancer treatment that shuts down the activity of the MTH1 enzyme has been highlighted in two separate papers published this week in Nature ¹ ².

Both the Swedish and Austrian teams found that blocking the enzyme in mouse models of cancer with first-in-class inhibitors suppressed tumour growth.

MTH1 is a protein known to overcome the incorporation of oxidised nucleotides into DNA, which otherwise can result in misparing, mutations and cell death.

Both teams set out to evaluate whether MTH1 might offer a general target for cancer treatments.

In the first study Thomas Helleday and colleagues, from Karolinska Institute, Stockholm, argued that a ‘de-personalized anticancer strategy’, targeting the cancer phenotype using a synthetic-lethal approach, might tackle the problem of intra-tumour heterogeneity and be widely applicable to a range of tumours ¹.

First the team identified inhibitors by screening compound libraries and identified ‘hits’ that inhibited MTH1 catalytic activity.

From this they isolated two small-molecule inhibitors of MTH1: TH287 and TH588.

In protein co-crystal structures they demonstrate that these inhibitors bound to the active sites of MTH1, causing the incorporation of oxidized dNRPs into cancer cells, resulting in DNA damage.

Furthermore, they showed both TH287 and TH588 selectively killed tumours in mice implanted with skin, colorectal and breast cancer tumours taken from human patients.

The inhibitors were found to be less toxic to several primary or immortalized cells.

“This is in agreement with MTH1 being required for cancer cell survival while being non-essential in untransformed cells,” write the authors.

Finally, the team tested TH588 in mice transplanted with BRAF mutated melanomas resistant to carboplatin, dacarbazine and vemurafenib, and showed mice responded with reduced tumour growth rates.

Since such melanomas are known to exhibit high numbers of somatic mutations, the finding was considered significant.

“Here, we observe that the MTH1 protein is required for efficient survival of cancer cells, whereas it is non-essential in untransformed cells.

To explain this phenomenon, we propose a model where dysfunctional redox regulation and ROS in cancer cells lead to an oxidized dNTP pool, which in turn requires the MTH1 protein to prevent incorporation and DNA damage after replication,” write the authors.

In the second study Giulio Superti-Furga and colleagues, from the Research Centre for Molecular Medicine of the Austrian Academy of Sciences, Vienna, found that loss of function of MTH1 impaired growth of KRAS tumour cells; while MTH1 over expression reduced sensitivity towards SCH51344 (a compound that suppresses anchorage-independent growth of RAS transformed fibroblasts) ².

Screening a kinase inhibitor collection for more potent MTH-1 inhibitors, the team identified (S)-crizotinib, an enantiome of a recently clinically approved anticancer agent, crizotinib. In the presence of (S)-crizotinib, tumour growth was suppressed in a mouse model of colon cancer.

“Removal of oxidized nucleotides by MTH1  may relieve cancer cells from proliferative stress and thereby represent a vulnerability factor and an attractive target for anticancer compounds” write the authors.

References:

1. H Gad, T Koolmeisten, A Jemth, et al. MTH1 inhibition eradicates cancer by preventing sanitation of the DNTP pool. Nature.

2. K Huber, E Salah, B Radic, et al. Stereospecific targeting of MTH1 by (S)-crizotinib as an anticancer strategy. Nature.