Most KRAS G12C mutant non-small cell lung cancer (NSCLC) patients experience clinical benefit from selective KRAS G12C inhibition, while patients with colorectal cancer (CRC) bearing the same mutation rarely respond. To investigate the cause of the limited efficacy of KRAS G12C inhibitors in CRC, we examined the effects of AMG510 in KRAS G12C CRC cell lines. Unlike NSCLC cell lines, KRAS G12C CRC models have high basal receptor tyrosine kinase (RTK) activation and are responsive to growth factor stimulation. In CRC lines, KRAS G12C inhibition induces higher phospho-ERK rebound than in NSCLC cells. Although upstream activation of several RTKs interferes with KRAS G12C blockade, we identify EGFR signaling as the dominant mechanism of CRC resistance to KRAS G12C inhibitors. The combinatorial targeting of EGFR and KRAS G12C is highly effective in CRC cells, patient-derived organoids and xenografts, suggesting a novel therapeutic strategy to treat KRAS G12C CRC patients.

The Drosophila adult posterior midgut has been identified as a powerful system in which to study mechanisms that control intestinal maintenance, in normal conditions as well as during injury or infection. Early work on this system has established a model of tissue turnover based on the asymmetric division of intestinal stem cells. From the quantitative analysis of clonal fate data, we show that tissue turnover involves the neutral competition of symmetrically dividing stem cells. This competition leads to stem-cell loss and replacement, resulting in neutral drift dynamics of the clonal population. As well as providing new insight into the mechanisms regulating tissue selfrenewal, these findings establish intriguing parallels with the mammalian system, and confirm Drosophila as a useful model for studying adult intestinal maintenance.

With the combination of KRAS G12C and EGFR inhibitors, KRAS is becoming a druggable target in colorectal cancer. However, secondary resistance limits its efficacy. Using cell lines, patient-derived xenografts, and patient samples, we detected a heterogeneous pattern of putative resistance alterations expected primarily to prevent inhibition of ERK signaling by drugs at progression. Serial analysis of patient blood samples on treatment demonstrates that most of these alterations are detected at a low frequency except for KRAS G12C amplification, a recurrent resistance mechanism that rises in step with clinical progression. Upon drug withdrawal, resistant cells with KRAS G12C amplification undergo oncogene-induced senescence, and progressing patients experience a rapid fall in levels of this alteration in circulating DNA. In this new state, drug resumption is ineffective as mTOR signaling is elevated. However, our work exposes a potential therapeutic vulnerability, whereby therapies that target the senescence response may overcome acquired resistance.

Amniotic mesenchymal stem cells (AMSCs) express octamer binding transcription factor 4 (Oct-4), which is necessary for maintaining the undifferentiated state of pluripotent stem cells. AMSCs also express CD29, CD44 and vimentin, which are specific markers of mesenchymal cells. We studied the biological characteristics and potential for cell therapy of AMSCs derived from 8-day-old chicken embryos. We induced the AMSCs to differentiate into adipocytes, osteoblasts and myocardial cells and used immunofluorescence, reverse transcription-polymerase chain reaction (RT-PCR) assays to detect the expressions of specific markers of AMSCs and differentiated cells. To assess the differentiation capacity of AMSCs, passage four cells were induced to differentiate into adipocytes, osteoblasts and myocardial cells. These results suggested that AMSCs isolated from chicken embryos exhibited the characteristics of multipotent stem cells. AMSCs, therefore, may be potential candidates for cellular transplantation therapy and tissue engineering.