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KRas mutation interactions with host immunity in malignant pleural effusion

Final Report Summary - KRASHIMPE (KRas mutation interactions with host immunity in malignant pleural effusion.)

KRAS is a cancer gene mutated in many human cancers of the lung, colon, pancreas and other organs (an estimated 33% of human tumors have mutations in the KRAS gene). KRAS mutations lead to uncontrolled tumor cell growth, rendering tumors more aggressive. At the same time, cancers with KRAS mutations are more resistant to anti-cancer therapies, including conventional chemotherapy, as well as novel biologics. The reasons behind these dismal characteristics of KRAS-mutant tumors that result in early cancer deaths are only partially known. For example, the relentless tumor cell proliferation caused by KRAS mutations can account for the enhanced growth of primary tumors with these mutations, but cannot explain why patients with these tumors exhibit more metastases and malignant pleural effusions (MPE; an aggressive form of tumor metastasis to the pleural space surrounding the lungs) and succumb to their disease earlier. In addition, while multiple clinical studies indicate that KRAS-mutant tumors are more refractory to drug treatment, the mechanisms of this resistance are largely unknown. Using mouse and cell models of human disease, we discovered that some mouse tumor cells have KRAS mutations, which are identical to those found in human cancers, while other types of murine tumor cells have normal KRAS genes. Moreover, we found that mouse tumor cells with KRAS mutations could induce MPEs in mice that appeared similar to MPEs from humans, while mouse tumor cells without KRAS mutations could not. When the mutant KRAS gene was suppressed in cells with the mutation by introduction of small inhibitory RNAs, the aggressive behavior of the tumor cells that leads to MPE development was also suppressed. In addition, when the mutant KRAS gene was isolated from cells with the mutation and transferred to cells with normal KRAS, cells acquired the aggressive behavior of MPE formation. Along other lines, we found that mouse cancer cells with KRAS mutations do not respond well to anti-cancer drugs compared with cells with normal KRAS and that this resistance is associated with enhanced activation of the nuclear factor (NF)-kB pathway that controls inflammation. Importantly, the mode and mediator-proteins of NF-kB activation was different in mouse cancer cells with or without KRAS mutations, rendering KRAS-mutant cancer cells refractory to treatment with available anti-cancer drugs. We are currently striving to better characterize these pathways of cancer-specific addiction between mutations in the KRAS gene and activation of the NF-kB pathway, hoping to come up with interventions designed to render human tumors with KRAS mutations amenable to therapy with existing anti-cancer drugs.