The Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway comprises four JAK kinases and seven STAT transcription factors. Among the latter, STAT3 is the best-known oncogene and its essential role in normal tissue makes its complete blockage useless for treatment due to severe side effects.
Macrophages are specialized immune cells that can either stimulate or inhibit inflammation. Studies in mice suggest that phosphoinositide 3-kinase γ (PI3Kγ), a key mediator in macrophage signaling pathways predominantly expressed in myeloid cells, may promote immune suppression both in inflammation and in the tumor microenvironment.
Prostaglandin E2 (PGE2) regulates inflammation and the tumor microenvironment, thought to happen through engagement with the E-type prostanoid EP2 and EP4 receptors, exerting immunosuppression in the tumor microenvironment. The simultaneous blockade of EP2 and EP4 – not blocking either alone – is needed to overcome this immunosuppressor effect.
Cyclin-dependent kinase 8 (CDK8) is implicated in both transcription and cellular response to environmental stress signals. Due to its association with the complex that sustains cell proliferation and viability, and its role in cancer cell stress response to radiotherapy and chemotherapy, CDK8 is considered a target to watch in cancer therapy.
Cyclin-dependent kinase 4 and 6 (CDK4 and CDK6) are validated targets for the treatment of ER+/HER2- breast cancer, but resistance to therapy is still a problem in these patients, with >20% of them developing intrinsic resistance and up to 70% developing acquired resistance within 3 years.
Interleukin-13 (IL-13) receptor subunit α2 (IL13RA2), one of the two major receptors for IL-13 is overexpressed in glioblastoma multiforme and other solid tumors and is correlated with poor prognosis.
Researchers at 1200 Pharma LLC have undertaken preclinical analysis of KRAS G12C inhibitors in clinical phases with the aim of finding an explanation for the differences observed in therapeutic efficacy in tumor sites other than lung, including lung-derived metastases. Results pointed to potency and pharmacokinetics as key drivers of efficacy.
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