Targeting cancer’s Achilles heel – the hunt for better treatments is still on
Despite giant strides in recent decades, we still have some way to go before we can claim to have suitable treatments for all types of cancers, especially at the most advanced stages. Fortunately, the field of cancer research is more buoyant than ever, and new therapeutic strategies are being developed by scientists across the globe.
Traditional treatments such as radiotherapy and chemotherapy can be efficacious, but they are non-selective and can make patients feel quite unwell from the side effects. In recent years, the scientific community has changed course to specifically target the root causes of cancer such as immune evasion or over-reliance on specific signaling pathways conferring cancerous cells unlimited growth ability.
What is synthetic lethality?
One of these new strategies harnesses a phenomenon called synthetic lethality. Two genes produce a synthetically lethal combination when the perturbation of either gene alone is viable but the perturbation of both genes simultaneously results in cell death. Maybe the most famous success story in this field is olaparib, a PARP inhibitor specifically targeting cancers driven by hereditary BRCA1/2 mutations. In this case one of the peturbations is caused by the cancer itself; the BRCA1/2 mutation. The addition of a drug “olaparib” disrupts the working of another pathway known to be synthetically lethal in combination with the BRRCA1/2 mutation. This selectively kills the cancer cells whilst sparing the patients healthy cells. Olaparib now offers first line treatment for many breast, ovarian and prostate cancers.
Building upon this success, we and other groups have recently investigated WEE1 inhibitors as a new approach to harness synthetic lethality for cancer treatment. The concept is very similar to PARP inhibitors, except that instead of BRCA1/2 we are targeting TP53-mutated tumors, a well-known oncogene found in more than 50% of all cancers.
So, does that mean this treatment could provide a cure to over half of all cancers? Well, as usual in scientific research, it’s a bit more complex than that…
WEE1 kinase inhibitors – What’s the state of play?
WEE1 and TP53 are both critical to the cell cycle. Whilst TP53 orchestrates the G1/S check point, WEE1 is one of the master regulators of the G2/M checkpoint, the last hurdle prior to mitosis. In the synthetically lethal situation where both checkpoints are silenced (i.e. TP53 mutation and WEE1 inhibition), then co-administering a DNA-damaging agent leads cancer cells to apoptosis. Healthy cells which have functional TP53 are on the other hand, left unscathed.
The theory sounds very promising, but in practice WEE1 inhibitors are facing big challenges. This is highlighted by the front runner molecule – adavosertib – experiencing major dose limiting toxicity effects and having been dropped off the AstraZeneca pipeline in July this year.
What next for WEE1 inhibitors?
Recent news about adavosertib clinical outcome should not undermine WEE1 as an oncology target. Indeed, many believe the toxicity observed in the clinic may be related to the non-specificity of the AstraZeneca asset, especially against other cell cycle kinases like PLK1. The jury is still out on WEE1 as a target and clinical results from other WEE1 inhibitors like those developed by Zentalis Pharmaceuticals, Debiopharm and Impact Therapeutics may help see the wood for the trees. One thing is certain, the race is on for 2nd generation WEE1 inhibitors.
Additional fundamental research will also be needed to help understand WEE1 inhibitors pharmacology. So far, most mechanism of action studies were carried out using adavosertib as a tool compound. Its poor selectivity means the conclusions drawn from these studies may need to be reconsidered. New specific tool compounds will be critical to support this work.
As with many oncology therapeutic interventions, the immune response is not to be forgotten. Several studies have already shown that combining WEE1 inhibition with immune checkpoint blockade improves efficacy in cancers such as SCLC.
To find out more about the recent developments in WEE1 therapeutics and typical medicinal chemistry efforts required to improve selectivity in drug discovery, check out my recent webinar: Structure-Based Drug Design Selective WEE1 inhibitors.
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