Combined Inhibition of Ddr1 and Cdk4/6 Induces Synergistic Effects In Er-Positive, Her2-Negative Breast Cancer With Pik3Ca/Akt1 Mutations

<p><strong>COMBINED INHIBITION OF DDR1 AND CDK4/6 INDUCES SYNERGISTIC EFFECTS IN ER-POSITIVE, HER2-NEGATIVE BREAST CANCER WITH <em>PIK3CA/AKT1</em> MUTATIONS</strong></p> <p>Maryam Shariati, M.S. Advisory Professor: Funda Meric-Bernstam, M.D.</p> <p>Molecular alterations in the phosphatidylinositol 3‑kinase (PI3K)/ serine/threonine protein kinase B (AKT) signaling pathway occur frequently in estrogen receptor–positive (ER-positive) breast tumors. Patients with ER-positive, human epidermal growth factor receptor 2–negative (HER2-negative) metastatic breast cancer are often treated with cyclin-dependent kinase (CDK4/6) inhibitors such as palbociclib in combination with endocrine therapy. Although this is a very effective regimen, disease progression ultimately occurs in most patients. Further, the modulators of palbociclib sensitivity remain unclear. The purpose of this study was to identify synthetic lethality partners that can enhance palbociclib’s antitumor efficacy in ER-positive breast cancer with PI3K pathway alterations.</p> <p>Using ER-positive isogenic breast cancer cell lines, we demonstrated that the efficacy of palbociclib is attenuated in the presence of <em>PIK3CA </em>or<em> AKT1</em> mutations. Using a shRNA library screen targeting cancer–­­­­related human kinases, we identified that downregulation of discoidin domain receptor 1 (<em>DDR1</em>), a tyrosine kinase active in various cancers, is synthetically lethal with palbociclib. <em>DDR1</em> knockdown by shRNA markedly reduced the growth of <em>PIK3CA </em>and<em> AKT1</em> mutant and wild-type (WT) ER-positive cell lines <em>in vitro</em>. In addition, DDR1 pharmacological inhibitor, 7rh benzamide, decreased cell growth and inhibited cell cycle progression in all cell lines, while selectively enhancing the sensitivity of <em>PIK3CA </em>and<em> AKT1</em> mutant cells to palbociclib. Combined treatment of palbociclib and 7rh further induced cell cycle arrest, decreasing PLK1, cyclin E2, and RB phosphorylation in <em>PIK3CA </em>and<em> AKT1</em> mutant cell lines. <em>In vivo</em>, 7rh significantly enhanced the antitumor efficacy of palbociclib. Similarly, reverse phase protein array (RPPA) analysis of the xenografts revealed a greater PLK1 reduction in a combined 7rh and palbociclib treatment group. Our data indicate that DDR1 inhibition can augment the cell cycle suppressive effect of palbociclib and could be an effective targeted therapy for ER-positive, HER2-negative breast cancers with PI3K pathway activation.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2020

Authors dc:creator

• shariati, maryam
• <p>0000-0003-1897-1553</p>

Contributors dc:contributor

• Funda Meric-Bernstam
• Debu Tripathy
• Lauren Byers

• Breast cancer
• HR-positve
• PIK3CA
• AKT1
• CDK4/6 inhibition
• palbociclib resistance
• DDR1
• targeted therapy
• PI3K pathway
• synthetic lethality
• Medicine and Health Sciences
• Translational Medical Research

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1084

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2140