# Preventing in vivo resistance to PI3K/AKT/mTOR inhibitors through Mediator kinase inhibition

> **NIH NIH R43** · SENEX BIOTECHNOLOGY, INC. · 2022 · $400,000

## Abstract

Dysregulation of the PI3K/AKT/mTOR pathway is one of the most common genetic alterations in cancer, found
in more than one third of all solid tumors. Inhibitors of the key components of this pathway (mTOR, PI3K, AKT)
have been developed; some of them have been approved for breast cancer and for certain other malignancies.
However, the benefits of these inhibitors are limited by the development of resistance, which arises either through
enzymatic changes within the pathway or by the activation of compensatory signal transduction pathways or
other transcriptional changes. Suppressing transcriptional resistance mechanisms could revitalize the use of
PI3K/AKT/mTOR inhibitors, with a potentially transformative impact for many cancer patients. We propose to
combine PI3K/AKT/mTOR inhibitors with a drug candidate that selectively inhibits CDK8/19 Mediator kinase, a
regulator of transcriptional reprogramming, the key process required for the emergence of drug resistance.
CDK8/19 inhibitors (CDK8/19i) suppress the emergence of resistance to different anticancer drugs. In
preliminary studies, xenograft tumors formed by PTEN-deficient breast cancer cells were treated with mTOR
inhibitor everolimus. Although tumor growth was fully arrested for the first 7-8 weeks, all the everolimus-treated
tumors subsequently resumed their growth, indicating the development of resistance. While treatment with a
CDK8/19i as a single agent had a modest effect on tumor growth, when combined with everolimus, the CDK8/19i
fully prevented the development of resistance over 150 days of treatment. Prevention of everolimus resistance
by the CDK8/19i was associated with the counteraction of transcriptomic effects of everolimus on both tumor
and stromal cells. We hypothesize that our selective CDK8/19i preclinical drug candidate will suppress the
development of resistance not only to mTOR but also to PI3K and AKT inhibitors, extending the duration of
remission and possibly producing cures. This Phase I SBIR program will determine if the CDK8/19i prevents the
development of in vivo resistance to mTOR inhibitor everolimus, PI3Kα inhibitor alpelisib, and AKT inhibitor
capivasertib, in estrogen receptor (ER)-positive and triple-negative breast cancers. Under Aim 1, we will test the
ability of the CDK8/19i to prevent the development of in vivo resistance to everolimus, alpelisib and capivasertib
in cell-line based ER-positive and triple-negative breast cancer xenografts. Immunohistochemistry and
transcriptomic analysis will be used to characterize the tumor- and stroma-based mechanisms of in vivo
resistance to PI3K/AKT/mTOR inhibitors, which are prevented by CDK8/19 inhibition. Under Aim 2, we will
determine if the CDK8/19i will prevent the development of in vivo resistance to the combination of everolimus
and CDK8/19i in different clinically relevant patient-derived xenograft (PDX) models of ER-positive and triple-
negative breast cancers. If the CDK8/19i prevents the emergence of in vivo ...

## Key facts

- **NIH application ID:** 10602700
- **Project number:** 1R43CA271996-01A1
- **Recipient organization:** SENEX BIOTECHNOLOGY, INC.
- **Principal Investigator:** Eugenia V Broude
- **Activity code:** R43 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $400,000
- **Award type:** 1
- **Project period:** 2022-09-12 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10602700

## Citation

> US National Institutes of Health, RePORTER application 10602700, Preventing in vivo resistance to PI3K/AKT/mTOR inhibitors through Mediator kinase inhibition (1R43CA271996-01A1). Retrieved via AI Analytics 2026-06-24 from https://api.ai-analytics.org/grant/nih/10602700. Licensed CC0.

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