# Maximizing the Effectiveness of PI3K Inhibitors in the Treatment of Pten null Cancers

> **NIH NIH R35** · DANA-FARBER CANCER INST · 2020 · $1,049,779

## Abstract

Project Summary/Abstract
In studying the PI3 Kinase isoform dependence of different tumor types, we made an extremely surprising
finding that now turns out to have considerable clinical importance. This finding forms the basis for this OIA
application. We discovered that tumors driven by the loss of the PTEN tumor suppressor are uniquely
dependent on the p110β isoform of PI3 Kinase. This finding likely explains why PI3K inhibitors first tested on
PTEN null tumors failed in the clinic, as they were poor p110β inhibitors. New p110b specific compounds are
now showing clinical promise. In attempting to understand the molecular mechanisms that uniquely couple
PTEN loss to p110β activation, we have uncovered a set of molecular mechanisms, which not only explains
how p110β is activated in response to PTEN loss but also suggests why the same tumors might quickly
become partially or even totally resistant to PI3K inhibition. Notably the same mechanisms clearly suggest
other drug targets, which can and should be attacked in combination with PI3K in PTEN null tumors. Our very
recent data identify 2 proteins that uniquely interact with p110β, and not with p110α, form a positive feedback
loop in the absence of PTEN. One of these proteins is the small ras family GTPase known as Rac, which
interacts with p110β but not p110α. We have recently shown that Rac localizes p110b to the lipid rafts where it
is activated. Thus Rac is an upstream activator of p110β. However Rac family members are unique in that
their activators, the Rac GEFs, are activated by the phosphoinositide products of PI3Ks. Thus Rac is also a
downstream effector of p110β. The interactions of Rac and p110β constitute the very definition of a positive
feedback loop. However, this leaves open how the Rac/p110β feedback loop is initiated- what activates
p110β/Rac in the first place. We have found that the activation event is dependent the small adapter protein
CRKL which is also a p110β specific binding protein. Activation of CRKL occurs via a SRC/p130Cas signaling
cascade that is also activated by PTEN loss. Notably SRC signaling renders cells resistant to PI3K inhibition.
Finally and most exciting we have found that p110b inhibitors synergize with immune checkpoint blockade. We
have generated data already showing the inhibitors of SRC RAC PAK (another downstream target of RAC)
lipid raft formation and immune checkpoints can all combine well with p110b inhibitors in vitro, and in some
cases, in vivo. This grant will focus more rigorous testing of new drug combinations on the one hand and on
the other hand, further refining our mechanistic understanding of the effects of PTEN loss to generate even
better combination therapy.

## Key facts

- **NIH application ID:** 9978752
- **Project number:** 5R35CA231945-02
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** THOMAS M ROBERTS
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,049,779
- **Award type:** 5
- **Project period:** 2019-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978752

## Citation

> US National Institutes of Health, RePORTER application 9978752, Maximizing the Effectiveness of PI3K Inhibitors in the Treatment of Pten null Cancers (5R35CA231945-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9978752. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*