Sep 24, 2026 · 10 min · 8 segments
Drugs that inhibit signaling via the PI3K pathway (e.g. alpelisib, capivasertib) can cause hyperglycemia. The mechanism of this ADR as well as the implications of which anti-diabetes medications are…
Today, we're going to talk a little bit about the management of hyperglycemia with drugs that inhibit the MAP kinase pathway.
So most of this is going to be about The PIK3CA-alpha inhibitor that's been approved for several years for PIK3CA-altered breast cancer, but also a little bit about capivacetib as well.
At least for me, until not too long ago, that was kind of where my knowledge stopped.
Phosphatidyl inositol 3 kinases are heterodimers, you know, transmembrane, or lipid kinases, sorry, not transmembrane.
It's something like 80% of hormone-positive breast cancers and many other cancers as well.
What I did not appreciate is that insulin, binding to the insulin receptor, also activates the phosphoenositol 3 kinase pathway.
And therefore, I knew this, I think most of us knew this, is that apelosib causing hyperglycemia is an on-target effect.
And so when... insulin binds its receptor and activates PI3K, the kinase, and then downstream, you end up leading to increased expression of glucose transporters to the cell surface to allow glucose to come in, as well as increasing glycogen synthesis and stopping gluconeogenesis to decrease your glucose pretty quickly.
So if you block that, whether it's a pellicid, as a PI3 kinase inhibitor, or capivacetib as an AKT inhibitor, which is what's directly stimulated after you activate the kinase pathway via PI3 kinase.
And what has been demonstrated in mice models is that using insulin to manage this hyper, or giving insulin back to, say, you have mice, you put them on a Pelosib or put them on a PI3 kinase inhibitor, you cause some hyperglycemia, you block that MAP kinase pathway.
If you add insulin to that, to those cells, you can actually overcome that MAP kinase pathway inhibition and increase the survival of those cancer cells.
So there's a really nice review article that goes through kind of the recommended treatment.
And what they suggest is insulin as the last line treatment for hyperglycemia from MAP kinase inhibition.
Today, we're going to talk a little bit about the management of hyperglycemia with drugs that inhibit the MAP kinase pathway.
So most of this is going to be about The PIK3CA-alpha inhibitor that's been approved for several years for PIK3CA-altered breast cancer, but also a little bit about capivacetib as well.
At least for me, until not too long ago, that was kind of where my knowledge stopped.
Phosphatidyl inositol 3 kinases are heterodimers, you know, transmembrane, or lipid kinases, sorry, not transmembrane.
It's something like 80% of hormone-positive breast cancers and many other cancers as well.
What I did not appreciate is that insulin, binding to the insulin receptor, also activates the phosphoenositol 3 kinase pathway.
And therefore, I knew this, I think most of us knew this, is that apelosib causing hyperglycemia is an on-target effect.
And so when... insulin binds its receptor and activates PI3K, the kinase, and then downstream, you end up leading to increased expression of glucose transporters to the cell surface to allow glucose to come in, as well as increasing glycogen synthesis and stopping gluconeogenesis to decrease your glucose pretty quickly.
So if you block that, whether it's a pellicid, as a PI3 kinase inhibitor, or capivacetib as an AKT inhibitor, which is what's directly stimulated after you activate the kinase pathway via PI3 kinase.
And what has been demonstrated in mice models is that using insulin to manage this hyper, or giving insulin back to, say, you have mice, you put them on a Pelosib or put them on a PI3 kinase inhibitor, you cause some hyperglycemia, you block that MAP kinase pathway.
If you add insulin to that, to those cells, you can actually overcome that MAP kinase pathway inhibition and increase the survival of those cancer cells.
So there's a really nice review article that goes through kind of the recommended treatment.
And what they suggest is insulin as the last line treatment for hyperglycemia from MAP kinase inhibition.
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