Resistance to abemaciclib is associated with increased metastatic potential and lysosomal protein deregulation in breast cancer cells.

Cyclin dependent kinase 4 and 6 inhibitors such as abemaciclib are routinely used to treat metastatic estrogen receptor positive (ER+) breast cancer. However, adaptive mechanisms inhibit their effectiveness and allow for disease progression. Using ER+ breast cancer cell models, we show that acquired resistance to abemaciclib is accompanied by increase in metastatic potential.

Modeling breast cancer proliferation, drug synergies, and alternating therapies.

Estrogen receptor positive (ER+) breast cancer is responsive to a number of targeted therapies used clinically. Unfortunately, the continuous application of targeted therapy often results in resistance, driving the consideration of combination and alternating therapies. Toward this end, we developed a mathematical model that can simulate various mono, combination, and alternating therapies for ER + breast cancer cells at different doses over long time scales.

Mathematically Modeling the Effect of Endocrine and Cdk4/6 Inhibitor Therapies on Breast Cancer Cells.

Mathematical modeling of cancer systems is beginning to be used to design better treatment regimens, especially in chemotherapy and radiotherapy. The effectiveness of mathematical modeling to inform treatment decisions and identify therapy protocols, some of which are highly nonintuitive, is because it enables the exploration of a huge number of therapeutic possibilities. Considering the immense cost of laboratory research and clinical trials, these nonintuitive therapy protocols would likely never be found by experimental approaches.

Caveolin-1 controls mitochondrial damage and ROS production by regulating fission - fusion dynamics and mitophagy.

As essential regulators of mitochondrial quality control, mitochondrial dynamics and mitophagy play key roles in maintenance of metabolic health and cellular homeostasis. Here we show that knockdown of the membrane-inserted scaffolding and structural protein caveolin-1 (Cav-1) and expression of tyrosine 14 phospho-defective Cav-1 mutant (Y14F), as opposed to phospho-mimicking Y14D, altered mitochondrial morphology, and increased mitochondrial matrix mixing, mitochondrial fusion and fission dynamics as well as mitophagy in MDA-MB-231 triple negative breast cancer cells. Further, we found that interaction of Cav-1 with mitochondrial fusion/fission machinery Mitofusin 2 (Mfn2) and Dynamin related protein 1 (Drp1) was enhanced by Y14D mutant indicating Cav-1 Y14 phosphorylation prevented Mfn2 and Drp1 translocation to mitochondria.