TY - JOUR
T1 - AKT/mTOR signaling modulates resistance to endocrine therapy and CDK4/6 inhibition in metastatic breast cancers
AU - Abu-Khalaf, Maysa M.
AU - Alex Hodge, K.
AU - Hatzis, Christos
AU - Baldelli, Elisa
AU - El Gazzah, Emna
AU - Valdes, Frances
AU - Sikov, William M.
AU - Mita, Monica M.
AU - Denduluri, Neelima
AU - Murphy, Rita
AU - Zelterman, Daniel
AU - Liotta, Lance
AU - Dunetz, Bryant
AU - Dunetz, Rick
AU - Petricoin, Emanuel F.
AU - Pierobon, Mariaelena
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - Endocrine therapy (ET) in combination with CDK4/6 inhibition is routinely used as first-line treatment for HR+/HER2− metastatic breast cancer (MBC) patients. However, 30–40% of patients quickly develop disease progression. In this open-label multicenter clinical trial, we utilized a hypothesis-driven protein/phosphoprotein-based approach to identify predictive markers of response to ET plus CDK4/6 inhibition in pre-treatment tissue biopsies. Pathway-centered signaling profiles were generated from microdissected tumor epithelia and surrounding stroma/immune cells using the reverse phase protein microarray. Phosphorylation levels of the CDK4/6 downstream substrates Rb (S780) and FoxM1 (T600) were higher in patients with progressive disease (PD) compared to responders (p = 0.02). Systemic PI3K/AKT/mTOR activation in tumor epithelia and stroma/immune cells was detected in patients with PD. This activation was not explained by underpinning genomic alterations alone. As the number of FDA-approved targeted compounds increases, functional protein-based signaling analyses may become a critical component of response prediction and treatment selection for MBC patients.
AB - Endocrine therapy (ET) in combination with CDK4/6 inhibition is routinely used as first-line treatment for HR+/HER2− metastatic breast cancer (MBC) patients. However, 30–40% of patients quickly develop disease progression. In this open-label multicenter clinical trial, we utilized a hypothesis-driven protein/phosphoprotein-based approach to identify predictive markers of response to ET plus CDK4/6 inhibition in pre-treatment tissue biopsies. Pathway-centered signaling profiles were generated from microdissected tumor epithelia and surrounding stroma/immune cells using the reverse phase protein microarray. Phosphorylation levels of the CDK4/6 downstream substrates Rb (S780) and FoxM1 (T600) were higher in patients with progressive disease (PD) compared to responders (p = 0.02). Systemic PI3K/AKT/mTOR activation in tumor epithelia and stroma/immune cells was detected in patients with PD. This activation was not explained by underpinning genomic alterations alone. As the number of FDA-approved targeted compounds increases, functional protein-based signaling analyses may become a critical component of response prediction and treatment selection for MBC patients.
UR - http://www.scopus.com/inward/record.url?scp=85148526643&partnerID=8YFLogxK
U2 - 10.1038/s41698-023-00360-5
DO - 10.1038/s41698-023-00360-5
M3 - Article
AN - SCOPUS:85148526643
SN - 2397-768X
VL - 7
JO - npj Precision Oncology
JF - npj Precision Oncology
IS - 1
M1 - 18
ER -