“Insulin receptor substrates 1 and 2 (IRS1/2) mediate mitogenic and antiapoptotic signaling from insulin-like growth factor 1 receptor (IGF-IR), insulin receptor (IR), and other oncoproteins. IRS1 plays a central role in cancer cell proliferation, its expression is increased in many human malignancies, and its upregulation mediates resistance to anticancer drugs. IRS2 is associated with cancer cell motility and metastasis. Currently, there are no anticancer agents that target IRS1/2. We present new IGF-IR/IRS-targeted agents (NT compounds) that promote inhibitory Ser-phosphorylation and degradation of IRS1 and IRS2. Elimination of IRS1/2 results in long-term inhibition of IRS1/2-mediated signaling. The therapeutic significance of this inhibition in cancer cells was shown while unraveling a novel mechanism of resistance to B-RAFV600E/K inhibitors. We found that IRS1 is upregulated in PLX4032-resistant melanoma cells and in cell lines derived from patients whose tumors developed PLX4032 resistance. In both settings, NT compounds led to the elimination of IRS proteins and evoked cell death. Treatment with NT compounds in vivo significantly inhibited the growth of PLX4032-resistant tumors and displayed potent antitumor effects in ovarian and prostate cancers. Our findings offer preclinical proof-of-concept for IRS1/2 inhibitors as cancer therapeutics including PLX4032-resistant melanoma. By the elimination of IRS proteins, such agents should prevent acquisition of resistance to mutated-B-RAF inhibitors and possibly restore drug sensitivity in resistant tumors.”
While melanomas with BRAF mutations can be targeted with a combination of BRAF inhibitors and MEK inhibitors, the treatment can have side effects such as fever, light sensitivity, and rashes. But early results of a phase I clinical trial suggest that BRAF-mutant melanomas could be treated safely and effectively with a new combination: LGX818, a BRAF inhibitor developed by Novartis and MEK162, a MEK inhibitor developed by Array BioPharma. Moreover, using these drugs together may decrease common side effects of targeted BRAF treatments, including skin toxicities and muscle and joint pain. A phase III trial of this new combination treatment is expected to begin later in 2013.
A clinical trial found that dabrafenib, a BRAF inhibitor, was far more effective in treating melanomas that have BRAF mutations than the chemotherapy drug dacarbazine, according to a report at an American Society of Clinical Oncology meeting. Patients treated with this drug lived without getting worse for 70% longer than those treated with dacarbazine (5.1 vs. 2.7 months, respectively). Moreover, compared to those treated with vemurafenib in other studies, dabrafenib-treated patients had less risk of another kind of skin cancer called squamous cell carcinoma. This suggests that dabrafenib, which is experimental, could be safer than vemurafenib, which is FDA approved.
A New England Journal of Medicine study found that vemurafenib, which was approved by the FDA in 2011, controlled melanomas in about half of people who had been previously treated for this disease. The trial included 132 repeat patients; tumors shrank in 47% of the patients and were not evident in 6% during the course of the trial. Vemurafenib is a BRAF inhibitor and about half of melanoma patients have BRAF mutations. While 26% of patients developed another kind of skin cancer called squamous cell carcinoma, these lesions were successfully removed surgically.
Primary source: http://www.nejm.org/doi/pdf/10.1056/NEJMoa1112302