# Targeting AKT-Mutant Human Cancers

> **NIH NIH R01** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $410,835

## Abstract

PROJECT SUMMARY/ABSTRACT
Mutations that activate phosphatidylinositol 3-kinase (PI3K) pathway signaling are among the most common
events in human cancer. This has spurred tremendous therapeutic development seeking approaches to
rationally inhibit this pathway in diverse malignancies. Despite these activities, and notwithstanding the recent
dramatic increase in our knowledge of the spectrum, type, and frequency of PI3K pathway alterations in human
cancer, broadly active targeted therapies for which biomarkers of sensitivity are available to facilitate patient
selection are still lacking. We must address this urgent clinical challenge to improve the survival of cancer
patients. We recently combined a unique institution-wide prospective clinical sequencing initiative with an
active early-phase clinical trial program to demonstrate that an oral and selective ATP-competitive pan-AKT
kinase inhibitor had significant single-agent activity in a multi-histology basket study of patients with AKT1
E17K-mutant advanced solid tumors. We went on to show in preliminary correlative studies that specific
genomic correlates of response and resistance to AKT inhibition in AKT-mutant cancers are varied. These
findings underscore the potential for developing unique therapeutic strategies targeting tumors with distinct
mutational drivers that converge on hyperactivated PI3K signaling. Yet, without an integrated clinical-
translational genomic approach to reveal the mechanisms underlying the dependence of solid tumors on
mutant AKT, the gap in our understanding will only widen. We propose to overcome this challenge by
establishing what conditions AKT inhibitor response and resistance in pre- and post-treatment tumor
specimens and longitudinally collected tumor-derived cell-free DNA from patients with AKT-mutant human
cancers. We will establish the genomic determinants of AKT inhibitor sensitivity. Then, we will identify which
genomic abnormalities, when acquired or selected for, mediate AKT inhibitor resistance. Finally, we will identify
and both functionally and clinically validate novel low-incidence activating mutations in AKT isoforms that
confer similar pathway dependence and inhibitor sensitivity, thereby expanding a predictive biomarker for
patient selection. Together, these studies seek to establish mutant AKT as a rational therapeutic target, and in
doing so, establish a clinical-translational genomic framework to facilitate effective, evidence-based precision
oncology in AKT-mutant cancers that can be extended to other molecularly defined populations of cancer
patients.

## Key facts

- **NIH application ID:** 9963152
- **Project number:** 5R01CA207244-05
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** David B. Solit
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $410,835
- **Award type:** 5
- **Project period:** 2016-07-05 → 2021-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9963152

## Citation

> US National Institutes of Health, RePORTER application 9963152, Targeting AKT-Mutant Human Cancers (5R01CA207244-05). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9963152. Licensed CC0.

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