Article Figures & Data
Figures
- FIGURE 1.
PI3K/AKT/mTOR signaling is regulated by intrinsic feedback. With AKT inhibition, intrinsic feedback inhibition mechanisms built into AKT signaling pathway are released, resulting in increased RTK surface expression and activation, primarily of HER3. With PI3K inhibition, same AKT feedback inhibition mechanisms are released; however, because of cross-talk between PI3K and MAPK pathway, release of feedback inhibition mechanisms along MAPK pathway also contribute to increased RTK expression and activation. These feedback patterns are influenced by multiple cellular factors and are thought to differ meaningfully across patient tumors, such that degree of change in expression cannot be known a priori.
- FIGURE 2.
EGFR PET probe measures effects on cellular EGFR surface expression after treatment with either PI3K inhibitor or AKT inhibitor. After 48 h of treatment with vehicle or PI3K inhibitor GDC-0941 (left) or AKT inhibitor GDC-0068 (right) at specified doses, cell lines were incubated with EGFR PET probe for 1 h, and binding was measured by γ-counting. Middle row reflects percentage change in EGFR expression relative to control. Westerns blots of EGFR and β-actin were obtained from cells under same treatment conditions.
- FIGURE 3.
Changes in EGFR PET probe binding correlate closely with protein expression changes. Comparison of binding of radiolabeled EGFR PET probe with EGFR/β-actin intensity measured by Western blot analysis after treatment of specified cell lines with increasing concentrations of GDC-0941 (left) or GDC-0068 (right). Linear regression was used to determine goodness-of-fit and coefficient of determination.
- FIGURE 4.
HER3 PET probe measures effect on cellular HER3 surface expression after treatment with either PI3K inhibitor or AKT inhibitor. After 48 h of treatment with vehicle or PI3K inhibitor GDC-0941 (left) or AKT inhibitor GDC-0068 (right) at specified doses, cell lines were incubated with HER3 PET probe for 1 h, and binding was measured by γ-counting. Middle row reflects percentage change in HER3 expression relative to control. Westerns blots of HER3 and β-actin obtained from cells under same treatment conditions.
- FIGURE 5.
Changes in HER3 PET probe binding correlate closely with protein expression changes. Comparison of binding of radiolabeled HER3 PET probe HER3/β-actin intensity measured by Western blot analysis after treatment of specified cell lines with increasing concentrations of GDC-0941 (left) or GDC-0068 (right). Linear regression was used to determine goodness-of-fit and coefficient of determination.
- FIGURE 6.
EGFR PET probe visualizes changes in EGFR expression with treatment of HCC70 tumors. HCC70 xenografts imaged with EGFR PET probe after treatment with vehicle (A), GDC-0941 (B), or GDC-0068 (C). Images normalized to 0.6 SUV. SUVmean of HCC70 xenografts imaged with EGFR PET probe after treatment (D) demonstrates change in SUV of 57% and 95% in comparison to vehicle, respectively, n = 4 for all groups, *P < 0.05. Change in SUVmean of GDC-0068– vs. GDC-0941–treated xenografts of 24%, #P < 0.05.
- FIGURE 7.
Imaging with HER3 PET probe versus EGFR PET probe demonstrates differential RTK expression in response to treatment with AKT inhibitor. MDAMB468 xenografts imaged with HER3 PET probe after treatment with vehicle (A) or GDC-0068 (B) demonstrate 108% increase in SUVmean (E),*P < 0.05. MDAMB468 xenografts imaged with the EGFR PET probe after treatment with vehicle (C) or GDC-0068 (D) demonstrate no significant change in SUVmean, n = 4 for all groups.
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