Selective Small Molecule Inhibition of P110α and δ Isoforms of PI3 Kinase Is Cytotoxic to Human AML Progenitors
Bibliographic record
Abstract
Abstract Abstract 1556 P110α, β, γ and δ isoforms are catalytic domains of phosphoinosityl-3-kinase (PI-3K) which is frequently constitutively active in blast cells from acute myeloid leukemia (AML) patients. RNA and protein from all 4 isoforms were ubiquitously expressed in 32 AML samples which also showed expression of p-Akt Ser473, indicating PI-3K activation. Treatment of AML patient blast cells (n=45) with the p110α selective inhibitor PI3-Kinase alpha inhibitor 2 and p110δ selective inhibitor PCN5603 (Piramed Pharma,UK) caused dose dependent kill of AML colony forming cells (CFC) and inhibition of p-Akt Ser473 expression. In contrast, the P110β and p110γ selective inhibitors TGX-221 and AS-604850 showed little AML CFC kill. AML samples were more sensitive to PI3-Kinase alpha inhibitor 2 and PCN5603 killing than normal bone marrow or normal peripheral blood (Median IC50=1.8μM for 45 AML-CFC and 4.3μM for 8 normal CFC for PI3-Kinase alpha inhibitor 2. Median IC50=1.9μM for 45 AML-CFC and 6.2μM for 10 normal CFC for PCN5603). There was no significant difference between the IC50 and IC90 of p110α and δ inhibitors against AML CFC from samples with or without the FLT3 ITD. There was a weak correlation between the IC50 of the PI3-Kinase alpha inhibitor 2 or the IC50 of PCN5603 and the ratio of pAkt/total Akt (R2 = 0.23 and 0.24, respectively, p<0.05). RNAi inhibition of p110α and p110δ decreased the corresponding isoform's RNA and protein expression and caused AML CFC kill and inhibition of p-Akt Ser473 expression. There was a strong correlation between the percent AML CFC kill and RNA knockdown (R2 = 0.67) and between inhibition of p-Akt and p110 protein expression (R2 = 0.90 for α and 0.82 for δ). Thus, p110α and δ inhibition may achieve selective targeting of malignant rather than normal CFCs. Furthermore, treatment of AML cells with PCN5603, decreased survival of AML long-term culture- initiating cells (AML LTC-IC). In contrast, less toxicity toward normal bone marrow LTC-IC was observed (IC50=0.08μM, ≤2μM and 1.33μM for 3 AML samples and IC50=3.09μM, 2.63μM, >10μM and >10μM for 4 normal bone marrows). Selective inhibition of p110α and δ isforms of PI-3K kills AML progenitors including candidate leukemic stem cells (AML LTC-IC) with relative sparing of analogous normal cells suggesting that these molecules could be therapeutic targets in AML. Disclosures: No relevant conflicts of interest to declare.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".