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Principal Investigator: Aritro Nath
Organization: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
Fiscal Year: 2024
Award: $88,666
Funding agency: National Cancer Institute
Abstract
Combining cyclin-dependent kinase (CDK) inhibitors with endocrine therapy improves outcomes for metastatic
estrogen receptor positive (ER+), HER2 negative, breast cancer patients. However, the value of this combination
in potentially curable earlier stage patients is variable. Our preliminary results examined the evolutionary
trajectories of early stage breast cancer tumors using single cell transcriptomic profiling of serial tumor biopsies
from a clinical trial of preoperative endocrine therapy alone (letrozole) or in combination with the cell cycle
inhibitor ribociclib. Resistant tumors with accelerated loss of estrogen signaling show up-regulation of the JNK
pathway, while those that maintain estrogen signaling during therapy show potentiation of CDK4/6 activation
consistent with ERBB4 and ERK signaling up-regulation. Cell cycle reconstruction identified that tumors cells
can reactivate during combination treatment, indicating stronger selection for a proliferative state. We
hypothesize that resistance to CDK4/6 inhibition in earlier stage breast cancer is driven by JNK MAPK
pathway stimulation and reactivation of the cell cycle through promotion of CDK6 expression or
decreased cell cycle inhibitor function. In Aim 1, we will use a new mechanistic model of CDK4/6 regulation
by cell cycle Inhibitors and Promoters (CIP) that couples estrogen and JNK signaling with cell cycle progression
to measure the mechanisms driving cell cycle activation in a series of isogenic cell lines sensitive and resistant
to CDK4/6 and endocrine inhibitors and in patient tumor cells. This analysis will reveal how distinct signaling
pathways contribute to cell cycle reactivation during estrogen, CDK4/6 and JNK inhibition treatments and provide
signatures of each resistant mechanism across cell types, over time and between systems. Aim 2 leverages our
collection of patient tumors from the FELINE clinical trial to discover the intracellular and intratumoral resistance
mechanisms driving proliferation. Fundamental resistance mechanisms will be measured in over ~300,000
patient cells from 360 tumor samples using single cell RNA sequencing data already in hand to identify core
intracellular signaling states that act alone or in concert to drive proliferation. Next, the population of cells within
each tumor will be analyzed to quantify intratumoral heterogeneity and how resistant populations differ in growing
or shrinking tumors during drug treatment. Applying CIP to project proliferation across patient tumor cells will
allow prediction of inhibitor strategies that most effectively block intracellular and intratumoral proliferation. Lastly,
Aim 3 will apply a series of JNK pathway drugs with clinical potential to design and test treatment strategies that
maintain durable inhibition of proliferation in ER+ cancer cells. Iterative feedback between mathematical models
and patient/experimental data serves to provide a deep understanding of cell cycle regulation and mechanisms
of dysregulation leading to resistance. Together, these experiments will reveal the balance between estrogen
and alternative mediated JNK signaling, and their roles in resistance and provide a guide for therapeutic regimes
with more durable control of cancer cell proliferation.
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