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Drug resistance is a perpetual problem in cancer therapy with many underlying mechanisms. Alterations in drug transport over the cancer cell membrane can severely alter intratumoral drug exposure, contributing to resistance. Here, we present the somatic mutational landscape of 48 ATP-binding cassette and 416 solute carrier transporter genes in a cohort (CPCT-02; NCT01855477) of 3290 patients with different types of advanced and metastasized cancer through analysis of whole genome and transcriptome sequencing. In order to identify potential stressor mechanisms, we stratified patients based on previous systemic therapies and subsequently investigated the enrichment of mutations and copy-number alterations of transporter genes. In tumors from patients pretreated with protein kinase inhibitors (PKIs), genes encoding for specific copper (SLC31A1 and SLC31A2, χ2-test adjusted p-values: 6.9e-09 and 2.5e-09) and nucleoside transporters (SLC28A2 and SLC28A3, χ2-test adjusted p-values: 3.5e-06 and 6.8e-07) were deleted significantly more frequently than in patients pretreated with chemotherapy. Moreover, we detected 16 transporters that were differentially expressed at RNA level between these treatment groups. These findings contradict mechanisms of selective pressure, as they would be expected to originate during treatment with chemotherapy rather than with PKIs. Hence, they might constitute primary drug resistance mechanisms and, therefore, warrant further study.

Additional file 2.

Purpose: Tyrosine kinase inhibitors (TKI) have poor efficacy in patients with glioblastoma (GBM). Here, we studied whether this is predominantly due to restricted blood–brain barrier penetration or more to biological characteristics of GBM. Patients and Methods: Tumor drug concentrations of the TKI sunitinib after 2 weeks of preoperative treatment was determined in 5 patients with GBM and compared with its in vitro inhibitory concentration (IC50) in GBM cell lines. In addition, phosphotyrosine (pTyr)-directed mass spectrometry (MS)-based proteomics was performed to evaluate sunitinib-treated versus control GBM tumors. Results: The median tumor sunitinib concentration of 1.9 μmol/L (range 1.0–3.4) was 10-fold higher than in concurrent plasma, but three times lower than sunitinib IC50s in GBM cell lines (median 5.4 μmol/L, 3.0–8.5; P = 0.01). pTyr-phosphoproteomic profiles of tumor samples from 4 sunitinib-treated versus 7 control patients revealed 108 significantly up- and 23 downregulated (P < 0.05) phosphopeptides for sunitinib treatment, resulting in an EGFR-centered signaling network. Outlier analysis of kinase activities as a potential strategy to identify drug targets in individual tumors identified nine kinases, including MAPK10 and INSR/IGF1R. Conclusions: Achieved tumor sunitinib concentrations in patients with GBM are higher than in plasma, but lower than reported for other tumor types and insufficient to significantly inhibit tumor cell growth in vitro. Therefore, alternative TKI dosing to increase intratumoral sunitinib concentrations might improve clinical benefit for patients with GBM. In parallel, a complex profile of kinase activity in GBM was found, supporting the potential of (phospho)proteomic analysis for the identification of targets for (combination) treatment.

Additional file 4: Table S1. Peptides significantly changing with 180 min of CIT (p 2), measured with a peptide microarray for patients 1–4 using a One-Way ANOVA test. In patient 5 none of the peptides were significantly changing with CIT. Peptides significantly altered, in patients 1–5 combined using a Mixed Model analysis, are shown in bold. UniProt Accession numbers, protein IDs and peptide sequence are given. Table S2. Phosphopeptides significantly changing with CIT (p

Checkpoint inhibition has emerged as a promising therapeutic strategy for several types of cancer. Immune-related adverse effects (irAEs) commonly involve the endocrine system. Distinguishing endocrine side effect-related symptoms from disease progression or treatment-related toxicity can be challenging. If not recognized in time, endocrine irAEs may be life-threatening. As the use of checkpoint inhibitors is expected to increase, there is a need for more awareness of endocrine irAEs amongst health care professionals. We describe three cases that illustrate the importance of timely recognition, patient education and the management of endocrinopathies. Two patients who were treated with the checkpoint inhibitor ipilimumab developed hypophysitis and subsequent episodes of hypocortisolism. These cases underline both the frequency of diagnostic delay and the importance of patient education with regard to glucocorticoid stress dosage. The third patient presented with diabetes mellitus after administration of nivolumab. A multidisciplinary approach is warranted to ensure optimal care for patients with endocrine irAEs.

The authors recently noticed that the affiliations for Valentina Vurchio, Andrea Bertotti, and Livio Trusolino were listed incorrectly. The correct author affiliation is shown here and has been corrected in the original article. The authors apologize for this error.

Three women, aged 18, 31 and 36 years, presented with hypertension while taking oral contraceptives. Each patient had received antihypertensive drugs. Blood pressure returned to normal within weeks of cessation of oral contraceptives. Although the reduction in hormone content seems to have reduced the risk of oral contraceptive-induced hypertension, there is still an increased risk. As the prevalence of hypertension in women aged under 45 is low, the possibility that the hypertension is caused by contraceptives should be considered in women of childbearing age. Discontinuation may cause a significant decrease in blood pressure and should be encouraged before commencing antihypertensive agents. Alternative methods of contraception include the progestogen-only pill or a mechanical contraceptive device.

Three women, aged 18, 31 and 36 years, presented with hypertension while taking oral contraceptives. Each patient had received antihypertensive drugs. Blood pressure returned to normal within weeks of cessation of oral contraceptives. Although the reduction in hormone content seems to have reduced the risk of oral contraceptive-induced hypertension, there is still an increased risk. As the prevalence of hypertension in women aged under 45 is low, the possibility that the hypertension is caused by contraceptives should be considered in women of childbearing age. Discontinuation may cause a significant decrease in blood pressure and should be encouraged before commencing antihypertensive agents. Alternative methods of contraception include the progestogen-only pill or a mechanical contraceptive device.