I decided to track down the exact pathway that cau

I decided to track down the exact pathway that causes leronlimab to disrupt DNA repair in tumors. I thought if AOH1996 breaking PCNA was successful in trials it could be paired with leronlimab to be more effective.

It starts with our old friend CCL4 binding to CCR5. This activates the PI3K/AKT/MTOR pathway which knocks down the p21 tumor suppressor and activates PCNA. Leronlimab would reverse this and increase the p21 tumor suppressor and downregulate activation of PCNA.

Like leronlimab doing what Keytruda does with PD-1/PDL-1, leronlimab may have the same level of activity as AOH1996 and AOH1996 would add nothing to leronlimab's effect. Then add in stopping migration of tumor cells, increasing natural killer T-cells to attack tumors and stopping other factors that protect tumor cells.

Quote:

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PI3Kβ regulated DNA replication through kinase-dependent and kinase-independent mechanisms. PI3Kβ was found in the nucleus, where it associated PKB. Modulation of PI3Kβ activity altered the DNA replication rate by controlling proliferating cell nuclear antigen (PCNA) binding to chromatin and to DNA polymerase δ. PI3Kβ exerted this action by regulating the nuclear activation of PKB in S phase, and in turn phosphorylation of PCNA negative regulator p21Cip. Also, p110β associated with PCNA and controlled PCNA loading onto chromatin in a kinase-independent manner. These results show a selective function of PI3Kβ in the control of DNA replication.
https://www.pnas.org/doi/10.1073/pnas.0812000...b++0pubmed

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