Possibly more appealing is to hunt the underlying mechanism for the genetic instability that causes the CNA (or any other cancer hallmark) to occur. It can prove very valuable to ask why they arose in the first place and examine if the cancer cells are addicted to any particular cellular process that enables them to cope with the instability-driving mechanism.
Here, the field has much to learn from paradigm-shifting approaches in personalised medicine that are now mainstays in the treatment of some solid tumours. Classic examples here being the vulnerability of homologous recombination-deficient cancers to PARP inhibitors, or immune checkpoint blockade in MSI-high colorectal cancers.
In Ross Chapman’s genome integrity group in Oxford, we have been building on the discovery of just such a synthetic lethal interaction. He found the genome instability in a group of high-risk breast cancers characterised by 17q amplification is driven by high protein levels of the 17q-resident-gene TRIM37. This inhibits the production of normal levels of a matrix of proteins called the pericentriolar material (PCM), which together with centrosomes form microtubule organising centres, required for mitotic spindle organisation.
Whereas most other cancers can undergo mitosis without centrosomes to organise their spindle, these 17q amplified-cancers without adequate PCM are entirely dependent on their centrosomes alone to be able to complete mitosis. They are therefore hypersensitive to, and killed by, drugs that inhibit the replication and production of new centrosomes during cell division.
Synthetic lethality and myeloma?
Myeloma is not a cancer with sweeping signatures of a particular type of DNA repair deficiency, but we do have clues.
As with most B cell malignancies, primary oncogenic translocations result from errors in scheduled immunoglobulin gene rearrangement during B cell development. Copy number signatures associated with higher number and complexity of CNA events predict for chromothripsis (a chromosome shattering event, seen in 24% of myelomas) and poorer outcomes.
The mechanism by which premalignant myeloma clones slowly accumulate their CNAs during the many years over which they emerge, is not yet understood. However, it is clear that the highest risk myelomas show higher CNA complexity, the presence of chromothripsis events, and gene expression signatures suggestive of abnormal fidelity during cell division.
We have become interested in pinpointing abnormal mitotic behaviour in the highest risk myelomas – behaviours that might explain both the genetic events that accumulate, but also lead us to abnormal behaviours that we might exploit as cancer-specific weaknesses in new therapies.
If we can pinpoint the underlying cause of the mitotic error accumulation that we see in high-risk myeloma, we may find that there are essential mechanisms on which the myeloma cell is abnormally dependant, even compared to other cancers.
Such a dependence may enable a myeloma cell to complete a cell division – despite accompanying errors – and could just be our next target.