Author ORCID Identifier

https://orcid.org/0000-0002-0417-0416

Date of Graduation

5-2020

Document Type

Thesis (MS)

Program Affiliation

Biomedical Sciences

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

Scott Kopetz, M.D., Ph.D.

Committee Member

Funda-Meric Bernstam, M.D.

Committee Member

Lawrence N. Kwong, Ph.D.

Committee Member

Imad Shureiqi, M.D., M.S.

Committee Member

Jennifer A Wargo, M.D., M.M.Sc.

Abstract

The phosphatidylinositol-3-kinase (PI3K) signaling pathway is activated in 20-40% colorectal cancers (CRC) through PTEN loss (PTENloss) and PIK3CA mutations (PIK3CAmut). Allosteric AKT inhibition with MK2206 monotherapy has been ineffective in CRC patients. We investigated the impact of MK2206 on pharmacodynamic (PD) markers and signaling pathways using reverse phase protein array (RPPA) on (1) paired tumor biopsies from a clinical trial of MK2206 in PI3K-altered metastatic CRC, (2) PTENlossCRC patient derived xenografts (PDX) treated with MK2206 or carrier, and (3) MK2206-treated cell lines. PD inhibition was deep in cell lines, less but significant in PDX, and only modest in patients. Expression of several receptor tyrosine kinases (RTKs) increased after AKT inhibition; insulin like growth factor 1 receptor (IGF1R) was significantly upregulated in patients, PDX and cell lines (P

The PI3K pathway also modulates tumor immune microenvironment and may influence response to emerging immunotherapies. Using quantitative immunohistochemistry, we found increased densities of effector T cells and increased expression of several checkpoints (including PD-L1) at the center of PI3K-altered early-stage MSS CRC. Subgroup analysis showed increased CD8+ cells among PIK3CAmut but not PTENloss cases. Using Agilent microarrays, we found higher PD-L1 and TIGIT mRNA levels in PI3K-altered MSS CRC (PPIK3CAmut MSS CRC patients derived clinical benefit more frequently than PIK3CA wild-type patients (50% vs 8.6%, P=0.015). We further showed synergism of combined PI3K and PD-1 inhibition in CT26 CRC mouse model.

We conclude that AKT inhibition in metastatic CRC induces FOXO-mediated adaptive upregulation of RTKs, namely IGF1R, possibly reactivating the pathway. PI3K-altered MSS CRC is an immunologically distinct subgroup with increased immune engagement, but also checkpoint upregulation, resulting in overall immunosuppression. Our results highlight potential targeted therapy and immuno-oncology combinations for PI3K-altered CRC patients.

Keywords

Colorectal cancer, PI3K, AKT, Adaptive resistance, Signaling pathway, Feedback loop, Immune microenvironment, PIK3CA mutation, PTEN loss

Available for download on Wednesday, April 28, 2021

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