Modulation of Pi3K-Akt Pathway In Colorectal Cancer

<p>The phosphatidylinositol-3-kinase (PI3K) signaling pathway is activated in 20-40% colorectal cancers (CRC) through PTEN loss (PTEN^loss) and <em>PIK3CA</em> mutations (<em>PIK3CA</em>^mut). 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) PTEN^lossCRC 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</p> <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 <em>PIK3CA</em>^mut but not PTEN^loss cases. Using Agilent microarrays, we found higher PD-L1 and TIGIT mRNA levels in PI3K-altered MSS CRC (PPIK3CA^mut MSS CRC patients derived clinical benefit more frequently than <em>PIK3CA</em> 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.</p> <p>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.</p>

Name thesis:degree_name

Masters of Science (MS)

Level thesis:degree_level

Thesis (MS)

Year dc:date.available

2020

Authors dc:creator

• Nusrat, Maliha
• <p>https://orcid.org/0000-0002-0417-0416</p>

Contributors dc:contributor

• Scott Kopetz, M.D., Ph.D.
• Funda-Meric Bernstam, M.D.
• Lawrence N. Kwong, Ph.D.

• Colorectal cancer
• PI3K
• AKT
• Adaptive resistance
• Signaling pathway
• Feedback loop
• Immune microenvironment
• PIK3CA mutation
• PTEN loss
• Medicine and Health Sciences
• Oncology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1003

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2052