BET inhibition induces vulnerability to MCL1 targeting through upregulation of fatty acid synthesis pathway in breast cancer.

Therapeutic options for treatment of basal-like breast cancers remain limited. Here, we demonstrate that bromodomain and extra-terminal (BET) inhibition induces an adaptive response leading to MCL1 protein-driven evasion of apoptosis in breast cancer cells. Consequently, co-targeting MCL1 and BET is highly synergistic in breast cancer models. The mechanism of adaptive response to BET inhibition involves the upregulation of lipid synthesis enzymes including the rate-limiting stearoyl-coenzyme A (CoA) desaturase. Changes in lipid synthesis pathway are associated with increases in cell motility and membrane fluidity as well as re-localization and activation of HER2/EGFR. In turn, the HER2/EGFR signaling results in the accumulation of and vulnerability to the inhibition of MCL1. Drug response and genomics analyses reveal that MCL1 copy-number alterations are associated with effective BET and MCL1 co-targeting. The high frequency of MCL1 chromosomal amplifications (>30%) in basal-like breast cancers suggests that BET and MCL1 co-targeting may have therapeutic utility in this aggressive subtype of breast cancer.

Chronic lingual papulosis: new, independent entity or "mature" form of transient lingual papillitis?

OBJECTIVE: Several acute, usually pediatric variants of edematous, symptomatic fungiform lingual papillitis have been reported since the 1990s, most notably transient lingual papillitis (TLP); but no chronic forms have been mentioned. Is there a chronic counterpart, akin to the older palatal examples of inflammatory papillary hyperplasia? The objective of this study was to clinicopathologically characterize a previously unreported entity with clustered, chronic fibrous papules (nonsyndromic) of the tongue. METHODS: Cases were collected from clinics in 2 dental schools. RESULTS: Five women and 4 men were identified with multiple, moderately firm, slightly pedunculated, normally colored masses clustered at the tip of the tongue (n = 4), covering the dorsal surface (n = 4) or on the lateral border (n = 1); 2 showed several erythematous or edematous papules (similar to TLP) admixed with fibrous papules. Patient ages ranged from 31 to 62 years (average 49) and all lesions had been present for many years. All lesions were asymptomatic except for the lateral border lesion, which presented with a burning sensation and mild tenderness (disappeared with antifungal medication). Five cases were associated with mouth breathing or a tongue-thrust habit; 4 were associated with geographic tongue or fissured tongue. Four papules were biopsied. All were composed of dense, avascular fibrous tissue with no or very few inflammatory cells; one showed focal mild neovascularity and edema. The lesion appeared to represent altered filiform papillae, more so than fungiform papillae. CONCLUSIONS: Chronic lingual papulosis (CLP) is an innocuous entity represented by focal or diffuse enlargement of numerous lingual papillae, primarily the filiform papillae. It appears to usually have an adult onset and most likely represents papillary reaction to very low-grade, chronic irritation or desiccation. Some cases with childhood onset, however, seem to be variations of normal anatomy. No treatment or biopsy is required, but a number of systemic disorders and syndromes must be ruled out before applying the CLP diagnosis.