Kinase-impaired BTK mutations are susceptible to clinical-stage BTK and IKZF1/3 degrader NX-2127.

Increasing use of covalent and noncovalent inhibitors of Bruton's tyrosine kinase (BTK) has elucidated a series of acquired drug-resistant BTK mutations in patients with B cell malignancies. Here we identify inhibitor resistance mutations in BTK with distinct enzymatic activities, including some that impair BTK enzymatic activity while imparting novel protein-protein interactions that sustain B cell receptor (BCR) signaling. Furthermore, we describe a clinical-stage BTK and IKZF1/3 degrader, NX-2127, that can bind and proteasomally degrade each mutant BTK proteoform, resulting in potent blockade of BCR signaling. Treatment of chronic lymphocytic leukemia with NX-2127 achieves >80% degradation of BTK in patients and demonstrates proof-of-concept therapeutic benefit. These data reveal an oncogenic scaffold function of mutant BTK that confers resistance across clinically approved BTK inhibitors but is overcome by BTK degradation in patients.

Resisting the Resistance: Navigating BTK Mutations in Chronic Lymphocytic Leukemia (CLL).

Bruton's tyrosine kinase (BTK) plays a key role in the B-cell receptor (BCR) signaling pathway and confers anti-apoptotic and proliferative properties to malignant B-cells in chronic lymphocytic leukemia (CLL). Small molecule BTK inhibitors were designed to bind BTK's active site and block downstream signaling. These drugs have now been used in the treatment of thousands of patients with CLL, the most common form of leukemia in the western hemisphere. However, adverse effects of early generations of BTK inhibitors and resistance to treatment have led to the development of newer, more selective and non-covalent BTK inhibitors. As the use of these newer generation BTK inhibitors has increased, novel BTK resistance mutations have come to light. This review aims to discuss previously known and novel BTK mutations, their mechanisms of resistance, and their relationship with patient treatment. Also discussed here are future studies that are needed to investigate the underlying cause allowing these mutations to occur and how they incite resistance. New treatments on the horizon that attempt to maneuver around these resistance mutations can be met with new resistance mutations, creating an unmet need for patients with CLL. Novel therapies and combinations that address all forms of resistance are discussed.

Assessment of SARS-CoV-2 entry in gingival epithelial cells expressing CD147.

SARS-CoV-2, the causative agent of the debilitating COVID-19, is mainly transmitted by first infecting nose and lung epithelial cells. The mouth is also believed to be a viral portal site since certain types of oral epithelial cells were shown to express ACE2 receptor. However, it is unclear whether oral epithelial cells are directly infected by SARS-CoV-2. In this study, we addressed whether epithelial cells of the oral gingiva were susceptible to infection. Interestingly, we found that KRT5+ and KRT18+ gingival epithelial cells do not express ACE2 but highly express TMPRSS2 and Furin as well as CD147, which was proposed to be an alternative receptor for SARS-CoV-2. However, using SARS-CoV-2 pseudoviruses containing the spike protein, we observed that gingival epithelial cells were not susceptible to infection due to the lack of ACE2 expression and the inability of CD147 to mediate viral entry. These results strongly suggest that epithelial cells from the gingiva are not susceptible to SARS-CoV-2 and CD147 is not a receptor for the SARS-CoV-2 virus. The susceptibility of oral cells from other oral structures under healthy and pathological conditions still needs to be confirmed to better understand the role of the oral cavity in COVID-19 infection and transmission.