RAS mutations are frequent in human cancer, especially in pancreatic, colorectal and non-small-cell lung cancers (NSCLCs). Inhibition of the RAS oncoproteins has proven difficult, and attempts to target downstream effectors have been hampered by the activation of compensatory resistance mechanisms. It is also well established that KRAS-mutant tumors are insensitive to inhibition of upstream growth factor receptor signaling. Thus, epidermal growth factor receptor antibody therapy is only effective in KRAS wild-type colon cancers. Consistently, inhibition of SHP2 (also known as PTPN11), which links receptor tyrosine kinase signaling to the RAS-RAF-MEK-ERK pathway, was shown to be ineffective in KRAS-mutant or BRAF-mutant cancer cell lines. Our data also indicate that SHP2 inhibition in KRAS-mutant NSCLC cells under normal cell culture conditions has little effect. By contrast, SHP2 inhibition under growth factor-limiting conditions in vitro results in a senescence response. In vivo, inhibition of SHP2 in KRAS-mutant NSCLC also provokes a senescence response, which is exacerbated by MEK inhibition. Our data identify SHP2 inhibition as an unexpected vulnerability of KRAS-mutant NSCLC cells that remains undetected in cell culture and can be exploited therapeutically.

The importance of tumor microenvironment (TME) as a relevant contributor to cancer progression and its role in the development of de novo resistance to targeted therapies has become increasingly apparent. However, the mechanisms of microenvironment-mediated drug resistance for nonspecific conventional chemotherapeutic agents, such as platinum compounds or antimetabolites, are still unclear.Here we describe a mechanism induced by soluble factors released by carcinoma-associated fibroblasts (CAFs) that induce the translocation of AKT, Survivin and P38 to the nucleus of tumor cells. These changes are guided to ensure DNA repair and the correct entrance and exit from mitosis in the presence of chemotherapy. We used conditioned media (CM) from normal-colonic fibroblasts and paired CAFs to assess dose response curves of oxaliplatin and 5-fluorouracil, separately or combined, compared with standard culture medium. We also evaluated a colony-forming assay and cell death to demonstrate the protective role of CAF-CM. Immunofluorescence confirmed the translocation of AKT, P38 and Survivin to the nucleus induced by CAF-soluble factors. We also have shown that STAT3 or P38 inhibition provides a promising strategy for overcoming microenvironment-mediated resistance. Conversely, pharmacologic AKT inhibition induces an antagonistic effect that relieves a cMET and STAT3-mediated compensatory feedback that might explain the failure of AKT inhibitors in the clinic so far.

We developed a two-protein immunohistochemical classifier that performs well at predicting the non-response to neoadjuvant treatment in rectal cancer.

Purpose: The aim of the study is blocking the recruitment of a protective stroma by altering the crosstalk between normal stromal cells and tumor cells for stripping tumors of the protection conferred by the microenvironment.Experimental Design: A transcriptomic analysis of cocultured normal colonic fibroblasts and colorectal tumor cells was performed. We focused on the study of molecules that mediate the communication between both compartments and that entail fibroblasts' activation and the alteration of the sensitivity to chemotherapy. We identified targets for the blocking of the tumor-stroma interaction. Finally, we tested, in vivo, the blockade of the tumor-stroma interaction in orthotopic models derived from patients and in models of acquired resistance to oxaliplatin.Results: IL1b/TGFb1 are the triggers for fibroblasts' recruitment and conversion into carcinoma-associated fibroblasts (CAF) in colorectal cancer. CAFs then secrete proinflammatory factors that alter sensitivity in tumor cells, activating JAK/STAT and PI3KCA/AKT pathways. Blocking such crosstalk with a neutralizing IL1b antibody and a TGFBR1 inhibitor is relieved by the TAK1-mediated activation of the noncanonical TGFb pathway, which induces a change in the cytokine/chemokine repertoire that maintains a sustained activation of AKT in tumor cells. TAK1 plus TGFBR1 inhibition blocks IL1b/TGFb1mediated fibroblast activation, decreasing the secretion of proinflammatory cytokines. In turn, tumor cells became more sensitive to chemotherapy. In vivo, the combination of a TAK1 inhibitor plus TGFBR1 inhibitor reduced the metastatic capacity of tumor cells and the recruitment of fibroblasts.Conclusions: Our findings provide a translational rationale for the inhibition of TAK1 and TGFBR1 to remove the chemoprotection conferred by CAFs.