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Comment by astazangasta | Hacker News Reader

People develop resistance to TKIs (tyrosine kinase inhibitors, the previous mode of therapy) within months; you could keep chasing the dragon, but the tumor is just going to keep doing the same thing, shedding whatever mutation you target. In this case you're not even targeting mutations that the tumor relies on (as you are with a TKI), so there's absolutely no fitness cost to the tumor to evade.

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Could you simultaneously target multiple mutations to reduce the risk of this? Similarly to using a cocktail of antibiotics to prevent the development of resistance.

i.e. the probability of shedding a single mutation is 1/x, but the probability of shedding two in the same organism is (1/x)^2, so targeting more mutations make it exponentially harder for the organism to adapt.

Yes, this reasoning is correct. Same principle applies to combination therapies for HIV, malaria, etc., where you're at risk of developing a resistant strain within the patient. Not sure why it isn't more common among cancer therapies. Maybe not enough unique targets?

Not enough unique drugs, difficulty determining mutations/susceptibility of tumour to drug, high side effect profile of drugs used in isolation and higher still in combination

Can you turn off a mutation's ability to adapt and mutate?

It would be called killing the tumour. The only way to destroy mutation is to destroy replication. We don't know how to increase the fidelity of DNA replication, and cancer cells have their error correct mechanisms all destroyed

hey - just want clarification. I thought TKIs like gleevec give an asymptomatic period of years - do you mean by "develop resistance" the initial seed population of cells that are resistant emerge from a (presumably clonal or near-clonal) pool within months?

Second: Do you know if clinically, agents like gleevec are primarily used as standalone or in conjunction with more aggressive (and, unfortunately, side-effect laden) therapies? I was always a bit aware of the pernicious "maintenance drug" status of gleevec, but presumably if you combine it with an orthogonal therapy you could get higher coverage and better statistical odds of sending the patient into remission.

Imatinib and other TKIs provide a range of effectiveness, from weeks/months to years. Nothing is forever (although the CD1 Ligands like ipilimumab etc show promise).

Mostly, the TKIs spread the Kaplan-Meyer curve out/lengthen it, but because it is still relying on the immune system to kill the cells (mostly) essentially TKIs are providing cellular senescence rather than cellular death. The bcr/abl mutation that imatinib targets is a cellular replication pathway, not s cell death pathway

ah... so standard chemo/rad isn't used because the immune response to clear out the senecent bastards will be compromised.

Agreed that for most tumor types targeting single antigens is a fool's errand, but the claim that "here is absolutely no fitness cost" for mutational evasion seem like is an overstatement. This is clearly false when using bacterial resistance to antibiotics as a more tractable proxy.

But what if the antigens are vital for the tumor ? What mutation are you referring to? Presumably the immune system will kill the cancerous cells ( shedding the mutation as well).

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