Clonal dynamics of BRAF-driven drug resistance in EGFR-mutant lung cancer

Activation of MAPK signaling via BRAF mutations may limit the activity of EGFR inhibitors in EGFR-mutant lung cancer patients. However, the impact of BRAF mutations on the selection and fitness of emerging resistant clones during anti-EGFR therapy remains elusive. We tracked the evolution of subclonal mutations by whole-exome sequencing and performed clonal analyses of individual metastases during therapy. Complementary functional analyses of polyclonal EGFR-mutant cell pools showed a dose-dependent enrichment of BRAF(V600E) and a loss of EGFR inhibitor susceptibility. The clones remain stable and become vulnerable to combined EGFR, RAF, and MEK inhibition. Moreover, only osimertinib/trametinib combination treatment, but not monotherapy with either of these drugs, leads to robust tumor shrinkage in EGFR-driven xenograft models harboring BRAF mutations. These data provide insights into the dynamics of clonal evolution of EGFR-mutant tumors and the therapeutic implications of BRAF(V600E) co-mutations that may facilitate the development of treatment strategies to improve the prognosis of these patients

Immune checkpoint inhibitors in lung cancer

Immune checkpoint inhibitors (ICI) have emerged as an important treatment strategy in lung cancer in recent years. Implementation and approval status of each approved ICI will be presented by summarizing the most important phase III studies of nivolumab, pembrolizumab, atezolizumab and durvalumab. ICI are used as mono- or combination therapy with chemotherapy according to programmed cell death 1 ligand 1 (PD-L1) status and therapy line

Plasma ignition and combustion

Electro-thermal-chemical (ETC) initiation and combustion offers the possibility to increase the performance of guns substantially as new propellant formulations and high loading densities (HLD) can be safely ignited and burnt in an augmented way. This paper reports investigations of burning phenomena in the low pressure region for JA2 and the effects of plasma interaction on ignition and study its influence on the burning rate. The comparison of transparent and opaque versions of the propellant is of special interest. Electrically produced plasma can strongly influence the ignition and combustion of solid propellants. Predominantly, plasma arcs influence strongly the burning of propellants by its radiation. The high intensity of the radiation initiates burning with short time delays in the mus-range and high conversion during exposure also in the case of a stable burning. Radiation can penetrate into the propellant interior and partially fragment at absorbing structures which could be artificially introduced or be inherently present as in the case of a JA2 propellant. Simplified approaches based on the heat flow equation and radiation absorption can explain these effects at least on a qualitative scale. Dynamic effects are understood by more sophisticated models

Acquired KRAS mutation and loss of low-level MET amplification after durable response to crizotinib in a patient with lung adenocarcinoma

Objectives: Resistance to tyrosine kinase inhibitor (TKI) therapy occurs inevitably in lung cancer patients with targetable genetic alterations. MET amplification has found to be an oncogenic driver in lung cancer with several reports showing response to MET TKI especially in cases with high-level amplification. Materials and methods: We report the case of a patient with lung adenocarcinoma harbouring low-level MET amplification and strong MET expression who was treated with crizotinib. Results: The patient developed a durable response to crizotinib. A KRAS mutation and loss of MET amplification was found in a new lesion at time of progression as a potential mechanism of acquired resistance. Conclusion: MET amplification is a continuous biomarker with responses to MET TM observed even in patients with low-level amplification. KRAS mutations may act as a resistance mechanism to MET inhibition in MET dependent lung cancer