Non–small cell lung cancers (NSCLCs) that harbor mutations within the epidermal growth factor receptor (EGFR) gene are sensitive to the tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib. Unfortunately, all patients treated with these drugs will acquire resistance, most commonly as a result of a secondary mutation within EGFR (T790M). Because both drugs were developed to target wild-type EGFR, we hypothesized that current dosing schedules were not optimized for mutant EGFR or to prevent resistance. To investigate this further, we developed isogenic TKI-sensitive and TKI-resistant pairs of cell lines that mimic the behavior of human tumors. We determined that the drug-sensitive and drug-resistant EGFR-mutant cells exhibited differential growth kinetics, with the drug-resistant cells showing slower growth. We incorporated these data into evolutionary mathematical cancer models with constraints derived from clinical data sets. This modeling predicted alternative therapeutic strategies that could prolong the clinical benefit of TKIs against EGFR-mutant NSCLCs by delaying the development of resistance.

Summary Most patients with advanced triple-negative breast cancer (TNBC) develop drug resistance. MYC and MCL1 are frequently co-amplified in drug-resistant TNBC after neoadjuvant chemotherapy. Herein, we demonstrate that MYC and MCL1 cooperate in the maintenance of chemotherapy-resistant cancer stem cells (CSCs) in TNBC. MYC and MCL1 increased mitochondrial oxidative phosphorylation (mtOXPHOS) and the generation of reactive oxygen species (ROS), processes involved in maintenance of CSCs. A mutant of MCL1 that cannot localize in mitochondria reduced mtOXPHOS, ROS levels and drug-resistant CSCs without affecting the anti-apoptotic function of MCL1. Increased levels of ROS, a by-product of activated mtOXPHOS, led to the accumulation of HIF-1α. Pharmacological inhibition of HIF-1α attenuated CSC enrichment and tumor initiation in vivo. These data suggest that 1) MYC and MCL1 confer resistance to chemotherapy by expanding CSCs via mtOXPHOS; and 2) targeting mitochondrial respiration and HIF-1α may reverse chemotherapy resistance in TNBC.

COVID-19-associated deaths were reported in the United States (1). Understanding the demographic and clinical characteristics of decedents could inform medical and public health interventions focused on preventing COVID-19-associated mortality. This report describes decedents with laboratory-confirmed infection with SARS-CoV-2, the virus that causes COVID-19, using data from 1) the standardized CDC case-report form (case-based surveillance) (https://www.cdc.gov/coronavirus/2019-ncov/php/ reporting-pui.html) and 2) supplementary data (supplemental surveillance), such as underlying medical conditions and location of death, obtained through collaboration between CDC and 16 public health jurisdictions (15 states and New York City). Case-based surveillanceDemographic and clinical data about COVID-19 cases are reported to CDC from 50 states, the District of Columbia, New York City, and U.S. territories using a standardized case-report form (case-based surveillance) or in aggregate. Data on 52,166 deaths from 47 jurisdictions among persons with laboratoryconfirmed COVID-19 were reported individually to CDC via case-based surveillance during February 12-May 18, 2020. Among the 52,166 decedents, 55.4% were male, 79.6% were aged ≥65 years, 13.8% were Hispanic/Latino (Hispanic), 21.0% were black, 40.3% were white, 3.9% were Asian, 0.3% were American Indian/Alaska Native (AI/AN), 0.1% were Native Hawaiian or other Pacific Islander (NHPI), 2.6% were multiracial or other race, and race/ethnicity was unknown for 18.0%. (Table 1). Median decedent age was 78 years (interquartile range (IQR) = 67-87 years). Because information about underlying medical conditions was missing for the majority of these decedents (30,725; 58.9%), data regarding medical conditions were not analyzed further using the case-based surveillance data set. Because most decedents reported to the supplementary data program were also reported to case-based surveillance, no statistical comparisons of the decedent characteristics between the data sets were made. * Underlying medical conditions include cardiovascular disease (congenital heart disease, coronary artery disease, congestive heart failure, hypertension, cerebrovascular accident/stroke, valvular heart disease, conduction disorders or dysrhythmias, other cardiovascular disease); diabetes mellitus; chronic lung disease (chronic obstructive pulmonary disease/emphysema, asthma, tuberculosis, other chronic lung diseases); immunosuppression (cancer, human immunodeficiency virus (HIV) infection, identified as being immunosuppressed); chronic kidney disease (chronic kidney disease, end-stage renal disease, other kidney diseases); neurologic conditions (dementia, seizure disorder, other neurologic conditions); chronic liver disease (cirrhosis, alcoholic hepatitis, chronic liver disease, end-stage liver disease, hepatitis B, hepatitis C, nonalcoholic steatohepatitis, other chronic liver diseases); obesity (body mass index ≥30 kg/m 2 ). Information was collected from decedent medical records or death certificates. ...

Acquired resistance to CDK4/6 small molecule inhibitors in breast cancer arises through mechanisms that are yet uncharacterized. In this study, we used a kinome-wide siRNA screen to identify kinases which when downregulated yields sensitivity to the CDK4/6 inhibitor ribociclib. In this manner, we identified PDK1 as a key modifier of ribociclib sensitivity in estrogen receptor-positive MCF-7 breast cancer cells. Pharmacological inhibition of PDK1 with GSK2334470 in combination with ribociclib or palbociclib, another CDK4/6 inhibitor, synergistically inhibited proliferation and increased apoptosis in a panel of ER+ breast cancer cell lines. Ribociclib-resistant breast cancer cells selected by chronic drug exposure displayed a relative increase levels of PDK1 and activation of the AKT pathway. Analysis of these cells revealed that CDK4/6 inhibition failed to induce cell cycle arrest or senescence. Mechanistic investigations showed that resistant cells coordinately upregulated expression of cyclins A, E and D1, activated phospho-CDK2 and phospho-S477/T479 AKT. Treatment with GSK2334470 or the CDK2 inhibitor dinaciclib was sufficient to reverse these events and restore the sensitivity of ribociclib-resistant cells to CDK4/6 inhibitors. Ribociclib in combination with GSK2334470 or the PI3Kα inhibitor alpelisib decreased xenograft tumor growth more potently than each drug alone. Taken together, our results highlight a role for the PI3K-PDK1 signaling pathway in mediating acquired resistance to CDK4/6 inhibitors.

Kinase inhibitors are accepted treatment for metastatic melanomas that harbor specific driver mutations in BRAF or KIT, but only 40–50% of cases are positive. To uncover other potential targetable mutations, we performed whole-genome sequencing of a highly aggressive BRAF (V600) and KIT (W557, V559, L576, K642, D816) wildtype melanoma. Surprisingly, we found a somatic BRAF L597R mutation in exon 15. Analysis of BRAF exon 15 in 49 tumors negative for BRAF V600 mutations as well as driver mutations in KIT, NRAS, GNAQ, and GNA11, showed that 2 (4%) harbored L597 mutations and another 2 involved BRAF D594 and K601 mutations. In vitro signaling induced by L597R/S/Q mutants was suppressed by MEK inhibition. A patient with BRAF L597S mutant metastatic melanoma responded significantly to treatment with the MEK inhibitor, TAK-733. Collectively, these data demonstrate clinical significance to BRAF L597 mutations in melanoma.