Oncogenic mutations in Kras occur in 40% to 45% of patients with advanced colorectal cancer (CRC). We have previously shown that chemotherapy acutely activates ADAM17, resulting in growth factor shedding, growth factor receptor activation, and drug resistance in CRC tumors. In this study, we examined the role of mutant Kras in regulating growth factor shedding and ADAM17 activity, using isogenic Kras mutant (MT) and wild-type (WT) HCT116 CRC cells. Significantly higher levels of TGF-a and VEGF were shed from KrasMT HCT116 cells, both basally and following chemotherapy treatment, and this correlated with increased pErk (phosphorylated extracellular signal regulated kinase)1/2 levels and ADAM17 activity. Inhibition of Kras, MEK (MAP/ERK kinase)1/2, or Erk1/2 inhibition abrogated chemotherapy-induced ADAM17 activity and TGF-a shedding. Moreover, we found that these effects were not drug or cell line specific. In addition, MEK1/2 inhibition in KrasMT xenografts resulted in significant decreases in ADAM17 activity and growth factor shedding in vivo, which correlated with dramatically attenuated tumor growth. Furthermore, we found that MEK1/2 inhibition significantly induced apoptosis both alone and when combined with chemotherapy in KrasMT cells. Importantly, we found that sensitivity to MEK1/2 inhibition was ADAM17 dependent in vitro and in vivo. Collectively, our findings indicate that oncogenic Kras regulates ADAM17 activity and thereby growth factor ligand shedding in a MEK1/2/Erk1/2-dependent manner and that KrasMT CRC tumors are vulnerable to MEK1/2 inhibitors, at least in part, due to their dependency on ADAM17 activity.

Sunitinib is one of the standard targeted therapies used in metastatic renal cell carcinoma. It is generally a reasonably tolerated oral systemic therapy but can be occasionally associated with life-threatening toxicities. We present a case of reversible posterior encephalopathy, which is a rare but recognised side effect of the treatment.

Mortality is decreasing for most cancers and the overall 5-year survival rate has now reached 50% ( Fig. 1 ). The 5-year survival rate in women (56%) is higher than that in men (43%) and this gender gap is also seen for 10-year survival rates (52% for women versus 39% for men). Figure 2 shows 5-year survival rates for common cancers in the UK. The highest 5-year survival rate for men is for testicular cancer (96%) and for women is for malignant melanoma (87%).

Although most oncology care takes place in secondary care, many patients are treated as outpatients. Oncology emergencies may occur when the patient is at home and the GP is often called. Therefore, it is important to know how to handle the common emergencies likely to arise. Remember that you are part of a team. For example, in many areas, there is a district or community nursing team available 24 hours a day who can be called upon to provide emergency nursing care, such as replacement dressings, or to attend to syringe drivers that have stopped functioning.

Supplementary Figures 1-5 from Oncogenic <i>Kras</i> Promotes Chemotherapy-Induced Growth Factor Shedding via ADAM17

Supplementary Table 1 from Oncogenic <i>Kras</i> Promotes Chemotherapy-Induced Growth Factor Shedding via ADAM17

Supplementary Figures 1-5 from Oncogenic <i>Kras</i> Promotes Chemotherapy-Induced Growth Factor Shedding via ADAM17

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