What question did this study set out to answer?

To examine the combined effects of MTORC1/2 inhibition and PIK3CA selective inhibition on colorectal cancer with PIK3CAH1047R mutations.

April 5, 2026

Abstract 5755: MTORC1/2 inhibition enhances STX-478, a PIK3CA H1047R mutant inhibitor, in PIK3CA H1047R mutant colorectal cancer

Key Points

To examine the combined effects of MTORC1/2 inhibition and PIK3CA selective inhibition on colorectal cancer with PIK3CAH1047R mutations.
Conducted a high throughput drug screen to identify AZD2014 as an MTORC1/2 inhibitor.
Treated CRC cell lines with STX-478 and AZD2014 to measure cell viability using WST assays.
Analyzed mouse-derived and patient-derived cancer organoids for treatment response and biochemistry of apoptosis and PI3K signaling.
Employed Glass’s Delta statistical test to assess effect sizes of treatment combinations.
Significant reduction in cell viability observed in both CRC cell lines with AZD2014 and further enhanced with the combination of STX-478.
In SW48PK, combination treatment significantly reduced phosphorylation of key proteins RPS6, AKT, and 4EBP1.
MDCOs exhibited decreased RPS6 phosphorylation compared to controls and single agents.
Patient-derived organoids showed a meaningful reduction in growth size when treated with the combination treatment.

Abstract

Abstract Background: STX-478, a PIK3CA mutant selective inhibitor, that we have previously shown to have promise in treating PIK3CAH1047R mutant colorectal cancer (CRC) models. A high throughput drug screen was performed and identified AZD2014, an MTORC1/2 inhibitor, to have enhanced response with STX-478. Here, we examine the combination of PI3K inhibition with MTORC1/2 inhibition in PIK3CAH1047R mutant colorectal cancer (CRC). Methods: CRC cell lines SW48 and SW48PK (Horizon Discovery; SW48 with a PIK3CAH1047R mutation) were treated with varying concentrations of STX-478 (250-750 nM) and AZD2014 (20-250 nM) and viability measured by WST was performed. PIK3CAH1047R mutant PDCOs were treated, imaged, and response was determined by measuring the change in longest diameter of the organoids over time. Glass’s Delta was used as a statistical test to measure the effect size of the different treatment groups. Mouse derived cancer organoids (MDCOs) were derived from Fc1 Apcfl/+ Pik3caH1047R murine colon tumors. MDCOs/PDCOs and CRC cell lines were treated with 750 nM or 500 nM STX-478 and 100 nM AZD2014, respectively, and collected for immunoblotting for apoptosis and PI3K proteins. Results: Both SW48 and SW48PK had a significant reduction in cell viability with treatment of single agent AZD2014 at 100 nM (SW48 p0.001, SW48PK p=0.005). When treated with combination of STX-478 and AZD2014, both cell lines had a significant reduction in cell viability (500 nM STX-478 with 100 nM AZD2014; SW48 p=0.002, SW48PK p0.001). For SW48PK, a significant reduction of phosphorylation of ribosomal protein S6 (RPS6; p0.001), AKT (p0.001), and 4EBP1 (p=0.002) were observed after treatment with the combination, while no significant difference was seen in SW48. MDCOs had a significant decrease in RPS6 compared to control and single agent STX-478 (p0.001). In PIK3CAH1047R mutant PDCOs, a significant reduction in relative change in diameter was observed in the combination treatment compared to control (relative change in diameter control versus combination: 30.2% vs -0.96%; Glass’s Delta = 1.67). PIK3CAH1047R mutant PDCOs also had a significant decrease in phosphorylation of 4EBP1 (p0.001) and RPS6 (p0.001). Conclusions: The combination of STX-478 and AZD2014 enhanced response in both 2D and 3D PIK3CAH1047R mutant CRC models and shows promise for combining MTORC1/2 with PIK3CA inhibition for PIK3CA mutant CRC. Future work should investigate STX-478 and MTORC1/2 inhibition in PIK3CA mutant CRC in vivo. Citation Format: Alexa E. Schmitz, Addison Zick, Cheri A. Pasch, Dustin A. Deming. MTORC1/2 inhibition enhances STX-478, a PIK3CA H1047R mutant inhibitor, in PIK3CA H1047R mutant colorectal cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 5755.

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Cite This Study

Schmitz et al. (Fri,) studied this question.

synapsesocial.com/papers/69d1fd8ea79560c99a0a39cd https://doi.org/https://doi.org/10.1158/1538-7445.am2026-5755

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