# Selectively targeting apoptosis in PIK3CA mutant colorectal cancers

> **NIH NIH R01** · DUKE UNIVERSITY · 2020 · $357,092

## Abstract

Project Summary
Approximately 20% of colorectal cancers (CRCs), representing 25,000 patients in the U.S. each year, harbor
activating driver mutations in the PIK3CA gene, which encodes the catalytic alpha subunit of
phosphatidylinositol-3-kinase (PI3K). These patients have particularly poor prognoses when treated with
standard-of-care chemotherapies and also fail to respond to single agent inhibitors of the PI3K pathway, a
problem that underscores the compelling need for more effective therapeutic strategies for PIK3CA mutant
CRC. Recently, by combining phosphoproteomic data from human CRC patients with combinatorial drug
screening in CRC cell lines, we discovered that inhibitors of the extracellular signal-regulated kinase (ERK)
pathway selectively sensitize PIK3CA mutant CRCs to inhibitors of the tyrosine kinase SRC without regard to
the mutational status of other commonly mutated genes, including KRAS and BRAF. Through mechanistic
studies, it was revealed that the selectivity of this combination for PIK3CA mutant CRCs owes to (1) SRC's
selective activation only in PIK3CA mutant cells, where its pharmacological inhibition cooperates with ERK
pathway inhibition to trigger apoptosis through the induction of the pro-apoptotic protein BIM, and (2) the fact
that PIK3CA mutant CRCs are “addicted” to chronic BIM suppression driven by constitutive PI3K activation,
and are thus vastly more sensitive to BIM induction than their PIK3CA wild-type counterparts. Acquired
resistance to combinations of SRC and ERK pathway inhibitors converges on the activation of the anti-
apoptotic protein BCL-XL, which directly antagonizes BIM. Upfront inhibition of BCL-XL in combination with
SRC and ERK pathway inhibition leads to penetrant cell killing while blocking the emergence of acquired
resistance. In this proposal, we build on these findings through a series of integrated studies examining (1) the
molecular mechanisms governing SRC activation and its cooperation with the ERK pathway in PIK3CA mutant
CRC; (2) the translational potential of combined SRC plus ERK pathway inhibition using studies in patient-
derived xenograft (PDX) models alongside correlative clinical studies in human patient tumors; and (3) the
ability of BCL-XL inhibition to reverse or block acquired resistance, alongside studies to elucidate the molecular
mechanisms governing BCL-XL activation in the resistant state. The work will define an essential survival
signaling network in PIK3CA mutant CRC and is expected to lead to the first selective targeted therapeutic
strategies for this aggressive disease subtype.

## Key facts

- **NIH application ID:** 9981691
- **Project number:** 5R01CA207083-05
- **Recipient organization:** DUKE UNIVERSITY
- **Principal Investigator:** Kris C. Wood
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $357,092
- **Award type:** 5
- **Project period:** 2016-08-12 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9981691

## Citation

> US National Institutes of Health, RePORTER application 9981691, Selectively targeting apoptosis in PIK3CA mutant colorectal cancers (5R01CA207083-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9981691. Licensed CC0.

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