GLS1 dependency in MYC over-expressing multiple myeloma: New target for therapy?

Dr Salomon Manier - Dana-Farber Cancer Institute, Boston, USA

We have presented this abstract about the MYC dependency in multiple myeloma. The concept is that MYC is a key oncogene of multiple myeloma. We know that it’s over-expressed in about 50% of the newly diagnosed patients. We know that it is associated with tumour progression from smouldering myeloma to multiple myeloma; the MYC translocations are associated with a poor outcome in multiple myeloma. It has a very broad role in the cancer cell but it’s one of these undruggable targets. Some attempts to directly target MYC were not completely successful in the clinic.

So we turned the problem a little bit differently and we tried to look at the gene dependencies in MYC over-expressing cells. So what we did for that is we used this large dataset called the Achilles Project developed at the Broad Institute in Boston and it’s a genome-wide loss of function screening across hundreds of cell lines. We classified the cell lines by MYC expression so the high MYC expression versus the low MYC expression. We looked at the loss of function that was affecting preferentially the cell lines with high MYC expression and we observed in the top hits MAX which is the co-activator of MYC, which was internal control, as well as two genes called GLS1 and SLC1A1. GLS1 and SLC1A1 are the genes involved in the glutamate pathway. So we’re interested, we confirmed that we have these differences of effect across the different cell types, across different cancer types. We did validate this with a GLS1 inhibitor that we treated cells with and the cells with a high expression of MYC were preferentially affected by this knock down of the GLS1.

Then we used that as our approach. We generated what we call an isogenic model. We used myeloma cell lines without expression of c-MYC and we over-expressed this c-MYC by lentiviral transduction. From these cell lines we confirmed that we have a good c-MYC signature in these cells and we performed a small molecule screen. We screened about 2,000 small molecules that are well annotated on these cell lines and we looked at the compounds that are able to preferentially affect the cell line with the high expression of MYC as compared to the isogenic controlled cell line. In that case we observed enrichment for mTOR inhibitor and the cell cycle inhibitor in some proportion.

So we were interested, we validated these mTOR inhibitors and we asked the question whether this two gene dependency could be synergistic. We treated the cells with this one compound called taurine 2 [?] and another compound which is a GLS1 inhibitor. We treated the cells and we see some synergistic effects at low concentration. We have more than an additive effect but a true synergistic effect so that’s interesting and it’s something we’re working on.

The hypothesis is that MYC induces a high translational activity and when you block the glutamate pathway and the mTOR pathway you block this protein translation activity and thus affect potentially preferentially the cells with the high MYC expression. So this is the hypothesis we are working on.

Would it be eventually made into a therapy or a target?

That’s the goal, to be able to translate these findings eventually into the clinic and why not develop clinical trials. Some of the mTOR and GLS inhibitors are used in clinic in other indications so that could be something we need to a little bit further validate these findings and establish a little bit more the functional path. But after that a clinical trial could be something that we would look forward to.