Cancer develops resistance to our most lethal drugs. Now we know how

Doug Hendrie

9/06/2020 4:51:27 PM

Combining the latest therapies with drugs that target DNA repair mechanisms could overcome cancer’s resistance to treatment.

Cancer cells dividing.
Cancer cells exposed to targeted therapies generate random genetic variation at a much higher rate.

Bacteria progressively develop resistance to antibiotics, as the huge selection pressure from our lethal drugs favours the tiny minority that can tolerate them.
Now researchers have discovered a very similar process at work in how cancer cells become resistant to targeted drugs – paving the way for combination therapies able to overcome the most tenacious cancers.
‘Resistance to treatment is arguably the major issue facing patients with advanced cancers, for whom even effective treatments ultimately fail. We have uncovered a fundamental survival strategy that cancer cells use to develop resistance, and which has given us new possible therapeutic strategies.’
That is Professor David Thomas, Cancer Research Theme Leader and Director of the Kinghorn Cancer Centre at the Garvan Institute. 
‘When cancer drugs are given, it stresses the cancer cell. We found the cancer cell tinkers with its own circuit board to try and find a configuration resistant to this new pressure,’ he told newsGP.
‘But it’s a trade-off – you tinker with anything and you usually damage it, but sometimes you make it better.
‘It’s as if you’re trying to fix a watch with a hammer.’
Professor Thomas’ team has found that cancer cells can turn on their error-prone DNA copying pathways in response to selection pressure from chemotherapy drugs, with the same process at work across melanoma, pancreatic cancer, sarcomas and breast cancer.
While our normal cells are constantly dividing, each time copying a DNA code the equivalent of three billion letters long with high precision in order to survive, the new research shows that cancerous cells do not need to do that.
‘When things are going pear-shaped, there is an advantage to tinker, as there’s a chance to survive the drug. This resistance appears to be programmed, not random,’ Professor Thomas said.
‘The changing environment [due to chemotherapy drugs] feeds back to increase the mutation rate within cancer cells.
‘The improved survival rates with cancers is due to public health measures and early detection – and also to the development of a really incredibly rich pipeline of exquisitely designed drugs.
‘If you match the right [cancer] mutations to the right drugs, you get very high response rates. But those rates – even where they are excellent – tend to be short-lived and eventually stop working.’
The discovery that stress-induced mutagenesis is at work in cancer, as it is in bacteria, opens the door to clever use of existing chemotherapy drugs in novel combinations, in order to make it far harder for cancers to adapt to the drug that is killing them – just as doctors do to reduce antibiotic resistance in bacteria. 
‘What we want to know now is how you take these drugs and increase their durability through combination therapy,’ Professor Thomas said.
‘For the first 20 years of these designer drugs, they’ve often been used as single agents. In the next 20 years, it will be how we combine them.’
In the new study, published in Science, Professor Thomas’ team found that the acquisition of mutations is regulated through the rapamycin (MTOR) signalling pathway, which acts as a stress-sensing rheostat. This pathway was present across many different cancer types and environments.
The team found that cancer cells from patients receiving targeted therapies had much higher levels of DNA damage than pre-treatment samples – even when these treatments did not directly damage DNA, according to study first author Dr Arcadi Cipponi.
‘Our experiments revealed that cancer cells exposed to targeted therapies … generate random genetic variation at a much higher rate than cancer cells not exposed to anti-cancer drugs,’ Dr Cipponi said.
‘This process is ancient – single-celled organisms, such as bacteria, use the same process to evolve when they encounter stress in their environment.
‘MTOR is a sensor protein that tells normal cells to stop growing because there is a stress in the environment. But we found that in the presence of a cancer treatment, MTOR signalling allowed cancer cells to change expression of genes involved in DNA repair and replication; for example, shifting from high-fidelity polymerases, the enzymes that copy DNA, to production of error-prone polymerases. 
‘This resulted in more genetic variation, ultimately fuelling resistance to treatment.’
The researchers found the shift to error-prone DNA repair and replication only lasted until the cancer cells mutated enough to resist the cancer drug.
Remarkably, the cancer cells switched back to high-fidelity pathways once they developed resistance, ensuring those surviving cells could survive and replicate once again.
In their study, Professor Thomas, Dr Cipponi and their team note that their observations are ‘consistent with a two-phase model for drug resistance, in which an initially rapid expansion of genetic diversity is counterbalanced by an intrinsic fitness penalty, subsequently normalising to complete adaptation under the new conditions’.
The finding points to the use of synthetic lethality strategies – where drugs are used to disrupt two genes simultaneously – as a promising avenue for overcoming cancer’s resistance to chemotherapy regimens.
Years in the making
It was almost two decades ago when Professor Thomas first had the idea that would lead to this research.
‘I couldn’t believe that random mutations weren’t themselves subject to selective pressure,’ he said. ‘I thought, that doesn’t really make sense, given the environment is constantly changing.
‘I wondered if there was a feedback loop from the environment, like an evolutionary capacitor which would upregulate or downregulate. It seemed a logical thing – but you can delude yourself.’
In the scientific literature, Professor Thomas found clear evidence for that process in single-celled organisms. This encouraged Professor Thomas and his team began to test the idea.
‘It’s clearly observable in those simple cells, so it was logical to ask if it happened in humans,’ Professor Thomas said. ‘That original idea was 19 years ago, and we started full time eight years ago, doing bench research.
‘It looks as though it makes sense. The molecular pathway we identified is a key evolutionary capacitor in yeasts. It fits the bill entirely.’
The discovery of the same ancient pathway in metazoans – multi-cellular organisms – is puzzling.
‘Single-celled organisms have this pathway, shuffling the genome around to produce new resistant mechanisms. But why would cells need to do this in metazoans? It’s really quite strange,’ Professor Thomas said. 
If cancer was a completely separate species, our immune system would likely make short work of it, Professor Thomas said.
‘Instead, it’s as if cancer cells are devolving,’ he said.
‘We’re made of 70 trillion cells – and then one goes rogue and instead of playing by the rule book, it starts to grow, following the laws of single-cell parasites. But it’s not a separate species, it’s a breakdown, a regression.
‘What’s that quote from Jurassic Park?  “Life finds a way”. It’s true for cancer.
‘It’s almost as if it’s become a separate species, cannibalising its host to propagate itself. It just wants to spread, like every other species.’ 
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Dr Kylie Fardell   21/06/2020 12:10:44 PM

Thanks very much for a fascinating article.