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Mantle Cell Lymphoma (MCL) and Chronic Lymphocytic Leukemia (CLL) are two aggressive subtypes of non-Hodgkin lymphomas (NHL) and make up about 7% and 6% of all NHL, respectively. One of the current treatments used in relapsed/refractory MCL and CLL patients is phosphoinositide 3-kinase (PI3K) inhibitors. PI3K enzymes have several isoforms of the catalytic subunit p110, which play a crucial role in signaling. The PI3K/AKT/mTOR signaling pathway is involved in various cellular processes, including cell growth, proliferation, and survival. It plays a key role in normal cellular function, but its dysregulation is also implicated in cancer development and progression. The PI3K inhibitors targeting p110 block this pathway and lead to cancer cell death. Unfortunately, they are limited in practice as they are known to cause off-target effects, cytotoxicity, with some patients develop resistance to them. Due to these limitations, further investigations need to be made with and there is a need for new therapeutic targets.

The Buckley lab recently discovered that E3 ligase, FBXO21, targets p85a for proteasomal degradation, a key component of the PI3K pathway. Inhibition of FBXO21decreases PI3K signaling. In collaboration with the Natarajan lab, a small-molecule inhibitor, 57-057, was developed to pharmacologically inhibit FBXO21. I aim to study how PI3K inhibitors, compared to 57-057 affect canonical PI3K signaling and its downstream proteins, and whether 57-057 works synergistically with PI3K inhibitors. In addition, because patients develop resistance to current PI3K inhibitors, I am generating resistant cell lines to determine the response to 57-057. Currently, we are treating HG3, CLL cell lines with PI3K inhibitors (Idelalisib, Buparlisib, Alpelisib) and 57-057, alone and combined, to determine the effects on the PI3K pathway. These studies will determine whether inhibition of p110 and FBXO21 leads to synergistic effects or differential signaling outcomes.