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BET inhibitors are promising therapeutic agents for the treatment of triple-negative breast cancer (TNBC), but the rapid emergence of resistance necessitates investigation of combination therapies and their effects on tumor evolution. Here, we show that palbociclib, a CDK4/6 inhibitor, and paclitaxel, a microtubule inhibitor, synergize with the BET inhibitor JQ1 in TNBC lines. High-complexity DNA barcoding and mathematical modeling indicate a high rate of de novo acquired resistance to these drugs relative to pre-existing resistance. We demonstrate that the combination of JQ1 and palbociclib induces cell division errors, which can increase the chance of developing aneuploidy. Characterizing acquired resistance to combination treatment at a single cell level shows heterogeneous mechanisms including activation of G1-S and senescence pathways. Our results establish a rationale for further investigation of combined BET and CDK4/6 inhibition in TNBC and suggest novel mechanisms of action for these drugs and new vulnerabilities in cells after emergence of resistance., Effective combination therapies to improve the efficacy of BET inhibitors are currently under investigation. Here, the authors examine palbociclib and paclitaxel as two promising candidates for combination therapies with BET inhibition in breast cancer and investigate the dynamics of resistance to these combinations through DNA barcoding and mathematical modelling.

ESR1 mutations were recently found to be an important mechanism of endocrine resistance in ER-positive (ER + ) metastatic breast cancer. To determine the clinicopathological features driving the emergence of the ESR1 mutations we studied plasma cfDNA and detailed clinical data collected from patients with metastatic breast cancer. Droplet Digital PCR was performed for the detection of the most common ESR1 mutations and PIK3CA mutations. Among the patients with ER + /HER2- disease, ESR1 mutations were detected in 30% of the patients. There were no associations between the pathological features of the primary disease or time to distant recurrence and the emergence of ESR1 mutations in metastatic disease. The prevalence of the ESR1 mutations was significantly associated with prior treatment with an aromatase inhibitor in the adjuvant or metastatic setting. The prevalence of the ESR1 mutations was also positively associated with prior fulvestrant treatment. Conversely, the prevalence of ESR1 mutations was lower after treatment with a CDK4/6 inhibitor. There were no significant associations between specific systemic treatments and the prevalence of PIK3CA mutations. These results support the evolution of the ESR1 mutations under the selective pressure of treatment with aromatase inhibitors in the adjuvant and metastatic settings and have important implications in the optimization of adjuvant and metastatic treatment in ER + breast cancer., Genetics: Drug treatment spurs new resistance mutations Treatment with aromatase inhibitors, a class of drugs that suppress the synthesis of estrogen, can drive the evolution of mutations in the estrogen receptor gene ESR1, leading to tumor resistance against hormone therapies. To better understand the emergence of ESR1 mutations, Rinath Jeselsohn from the Dana-Farber Cancer Institute in Boston, Massachusetts, USA, and coworkers tested tumor DNA contained within blood samples from 155 women with metastatic breast cancer. They found ESR1 mutations rarely in women with any molecular subtype of cancer other than estrogen receptor-positive disease. Nothing about the primary tumor predicted who would develop ESR1 mutations; however, treatment with an aromatase inhibitor was associated with mutations arising. The findings highlight the need to develop therapeutic regimens that reduce the selective pressure for ESR1 mutations and/or target these mutations directly.

Lenalidomide is an immunomodulatory drug related to thalidomide that has recently been reported to have significant single agent activity in relapsed CLL, with response rates of 35-50% including some complete responses1,2. The mechanism of action is unknown but appears to be immune-mediated given that lenalidomide alters cytokine levels and stimulates T and NK cell function, and lacks cytotoxicity against CLL in vitro3. In CLL patients, the administration of lenalidomide can be associated with tumor flare, a syndrome of painful enlarging lymphadenopathy, increased white count, fever, and rash1,2. This tumor flare can potentially escalate to become life-threatening, with renal insufficiency, tumor lysis or a systemic inflammatory response4,5. The mechanism of tumor flare remains unknown.

The physiological roles of phospholipase C (PLC) β2 in hematopoiesis, leukocyte function, and host defense against infection were investigated using a mouse line that lacks PLC β2. PLC β2 deficiency did not affect hematopoiesis, but it blocked chemoattractant-induced Ca2+release, superoxide production, and MAC-1 up-regulation in neutrophils. In view of these effects, it was surprising that the absence of PLC β2 enhanced chemotaxis of different leukocyte populations and sensitized thein vivoresponse of the PLC β2-deficient mice to bacteria, viruses, and immune complexes. These data raise questions about the roles that PLC β2 may play in signal transduction induced by chemoattractants in leukocytes.