TP53 gain-of-function mutations promote osimertinib resistance via TNF-α-NF-κB signaling in EGFR-mutated lung cancer.

EGFR tyrosine kinase inhibitors (TKIs) are effective against EGFR-mutated lung cancer, but tumors eventually develop resistance to these drugs. Although TP53 gain-of-function (GOF) mutations promote carcinogenesis, their effect on EGFR-TKI efficacy has remained unclear. We here established EGFR-mutated lung cancer cell lines that express wild-type (WT) or various mutant p53 proteins with CRISPR-Cas9 technology and found that TP53-GOF mutations promote early development of resistance to the EGFR-TKI osimertinib associated with sustained activation of ERK and expression of c-Myc. Gene expression analysis revealed that osimertinib activates TNF-α-NF-κB signaling specifically in TP53-GOF mutant cells. In such cells, osimertinib promoted interaction of p53 with the NF-κB subunit p65, translocation of the resulting complex to the nucleus and its binding to the TNF promoter, and TNF-α production. Concurrent treatment of TP53-GOF mutant cells with the TNF-α inhibitor infliximab suppressed acquisition of osimertinib resistance as well as restored osimertinib sensitivity in resistant cells in association with attenuation of ERK activation and c-Myc expression. Our findings indicate that induction of TNF-α expression by osimertinib in TP53-GOF mutant cells contributes to the early development of osimertinib resistance, and that TNF-α inhibition may therefore be an effective strategy to overcome such resistance in EGFR-mutant lung cancer with TP53-GOF mutations.

Mutant forms of EGFR promote HER2 trafficking through efficient formation of HER2-EGFR heterodimers.

INTRODUCTION: Human epidermal growth factor receptor 2 (HER2) forms homodimers and is retained at the surface of cancer cells positive for HER2 amplification. The dimerization, internalization, and intracellular trafficking of HER2 in cancer cells without HER2 amplification have remained uncharacterized, however. MATERIALS AND METHODS: HER2 homodimers and heterodimers were detected in various cell lines with the use of an in situ proximity ligation assay. The effects of wild-type or mutant forms of epidermal growth factor receptor (EGFR) on intracellular trafficking of HER2 were examined by live-cell imaging. The sensitivity of cell lines without HER2 amplification to ado-trastuzumab emtansine (T-DM1), an anti-HER2 (trastuzumab)-cytotoxic drug conjugate (ADC) was also investigated. RESULTS: HER2 preferentially formed heterodimers with EGFR rather than homodimers and was rapidly internalized together with EGFR in cells without HER2 amplification. HER2-EGFR heterodimers were more abundant and HER2 was more efficiently transferred to lysosomes in such cells with than in those without EGFR activating mutations. T-DM1 showed a high cytotoxic efficacy in the cells with EGFR mutations, suggesting that mutant forms of EGFR promote the transfer of HER2-bound T-DM1 to lysosomes through efficient formation of HER2-EGFR heterodimers. CONCLUSION: Our findings reveal that HER2 trafficking is affected by EGFR, especially by mutant forms of the receptor, and they provide a rationale for the use of HER2-targeting ADCs in the treatment of EGFR-mutated lung cancer.

[Preparation of a manual treatment of pressure ulcers which draws attention to moisture of the affected part].

As for pressure ulcers care, prevention is the most important approach. However, pressure ulcers, might develop despite enough care, depending on each person's physical condition. As for the treatment of pressure ulcers, maintenance of a moderately moist environment (60-70%) is quite important. We propose the use of ointment to control the moisture of a pressure ulcer environment. One ointment base absorbs moisture, while another provides moisture. We have prepared a manual that allows the user to select the medicine according to the degree of moisture of the affected part. When the moisture cannot be regulated with one ointment, it can be adjusted by mixing two or more ointments. In choosing a drug for external use, it is important to pay attention not only to the effect of the main ingredient but also to the physicochemical properties of the ointment base that serves as vehicle for that active component.

[Preparation of a manual treatment of pressure ulcers which draws attention to moisture of the affected part].

As for pressure ulcers care, prevention is the most important approach. However, pressure ulcers, might develop despite enough care, depending on each person's physical condition. As for the treatment of pressure ulcers, maintenance of a moderately moist environment (60-70%) is quite important. We propose the use of ointment to control the moisture of a pressure ulcer environment. One ointment base absorbs moisture, while another provides moisture. We have prepared a manual that allows the user to select the medicine according to the degree of moisture of the affected part. When the moisture cannot be regulated with one ointment, it can be adjusted by mixing two or more ointments. In choosing a drug for external use, it is important to pay attention not only to the effect of the main ingredient but also to the physicochemical properties of the ointment base that serves as vehicle for that active component.