“Patients with advanced or metastatic melanoma have been able to live longer cancer-free lives because of several new therapies approved over the last decade, such as BRAF and MEK inhibitors. However, despite the success of these targeted agents, most patients eventually develop drug resistance and their cancer regrows. A team of researchers at Moffitt Cancer Center have been working to learn more about how melanoma becomes resistant to BRAF inhibitors in order to develop new treatment strategies. They tested whether a drug targeting heat shock protein 90 (HSP90) combined with the BRAF inhibitor vemurafenib could be a safe and potentially effective strategy to treat patients with melanoma. Their study was published online ahead of print in Clinical Cancer Research.”
“Powerful drugs known as BRAF-inhibitors have been crucial for melanoma patients, saving lives through their ability to turn off the BRAF protein’s power to spur cancer cell growth.
“Yet they often work for only a year or less. Scientists know some of the DNA mutations that cause the drug resistance, but scientists have not been able to determine the underlying cause of the resistance in as many as a third of these patients. As a result, identifying genomic-based follow-up therapies for these patients has been a challenge.
“Researchers at The University of Texas MD Anderson Cancer Center may have found a way to more accurately predict which patients will likely respond to genomic-based follow-up therapies, by looking at unique ‘protein patterns’ in melanoma patients.
” ‘There are patients whose DNA does not reveal how their melanomas became resistant to BRAF inhibitors,’ said Lawrence Kwong, Ph.D., instructor in Genomic Medicine at MD Anderson. ‘So we looked at patterns of changes in 150 proteins which can give clues to the causes of resistance, even when DNA sequencing data is uninformative.’ “
“Clinical trials to test the new drugs in patients should begin as early as 2015.
“Existing drugs target faulty versions of a protein called BRAF which drives about half of all melanomas, but while initially very effective, the cancers almost always become resistant to treatment within a year.
“The new drugs – called panRAF inhibitors – could be effective in patients with melanoma who have developed resistance to BRAF inhibitors.
“The new study was funded by the Wellcome Trust and Cancer Research UK, and jointly led by scientists at The Institute of Cancer Research, London, and the Cancer Research UK Manchester Institute.
“It is published in the prestigious journal Cancer Cell today.
“The researchers showed that the new drugs – provisionally named CCT196969 and CCT241161 – stopped the growth of BRAF-driven melanomas, including those that had stopped responding to currently available BRAF-targeted drugs.”
“Half of melanoma patients with the BRAF mutation have a positive response to treatment with BRAF inhibitors, but nearly all of those patients develop resistance to the drugs and experience disease progression.
“Now, a new preclinical study published online ahead of print in the Journal of Clinical Investigation from Penn Medicine researchers found that in many cases the root of the resistance may lie in a never-before-seen autophagy mechanism induced by the BRAF inhibitors vermurafenib and dabrafenib. Autophagy is a process by which cancer cells recycle essential building blocks to fuel further growth. Block this pathway with the antimalarial drug hydroxycholoroquine [sic] (HCQ), the authors found, and the BRAF inhibitors will be able to do their job better…
“Based on these promising preclinical results, Dr. Amaravadi and his team have already launched a clinical trial for patients with advanced BRAF mutant melanoma to see how well-tolerated HCQ is with the BRAF inhibitor vemurafenib. ‘So far,’ he said, ‘we are seeing a benefit to patients and low toxicity.’ “
Because melanomas can quickly resist BRAF inhibitor drugs alone or in combination with MEK inhibitors, researchers are testing a new combination treatment: the BRAF inhibitor vemurafenib and PX-866, which inhibits a cancer pathway called PI3K. In a phase I/II clinical trial of 19 people with melanomas that have BRAF mutations, the vemurafenib/PX-866 combination shrank tumors in 10 of them. These findings were presented at the 10th International Congress of the Society for Melanoma Research in Philadelphia. However, while results so far are encouraging, it will take larger trials to see if this new combo treatment really overcomes drug resistance in melanomas. This ongoing trial is still accepting new participants.
Two new studies show that several different genetic mutations can make melanoma tumors resist drugs known as BRAF inhibitors, complicating treatment. These mutations are in genes that are part of the ‘MAPK pathway.’ The first study was on BRAF-inhibitor resistant melanomas from 45 people. In about half of the tumors, one of a set of three genes (MEK1, MEK2, MITF) was abnormal, and in three of the tumors more than one was abnormal.
The second study compared melanomas before and after resistance to combination treatment with both BRAF and MEK inhibitors. Tumors from three of the five people in the study developed genetic abnormalities that were not seen before treatment. On a positive note, when cells from resistant melanomas with both BRAF and MEK mutations were grown in the laboratory, they responded to a drug that inhibits a related protein called ERK.
The mutations in this study were all found in genes that code for proteins in the MAPK pathway, a particular group of proteins in a cell that work together to control cell multiplication that can lead to tumor growth. Knowing exactly which mutations a melanoma has will help doctors target it with the right combination of treatments.
American Association for Cancer Research | Oct 22, 2013
Even though about half of melanomas have BRAF mutations, some of these still fail to respond to BRAF inhibitors. Now, there may be a way to tell whether BRAF inhibitors are working, according to findings presented at the 2013 International Conference on Molecular Targets and Cancer Therapeutics. The researchers found that a BRAF inhibitor kept tumors from growing in six out of nine people with BRAF-mutant melanomas, and that those who benefitted from the treatment also had less activation of a protein called S6 at two weeks. If this link is verified in large clinical trials, S6 activation levels could predict BRAF inhibitor effectiveness during the early stages of treatment.
O'Connell MP, Marchbank K, Webster MR, Valiga AA, et al. Cancer Discovery. Oct 8, 2013.
“An emerging concept in melanoma biology is that of dynamic, adaptive phenotype switching, where cells switch from a highly proliferative, poorly invasive phenotype to a highly invasive, less proliferative one. This switch may hold significant implications not just for metastasis, but also for therapy resistance. We demonstrate that phenotype switching and subsequent resistance can be guided by changes in expression of receptors involved in the non-canonical Wnt5A signaling pathway, ROR1 and ROR2. ROR1 and ROR2 are inversely expressed in melanomas and negatively regulate each other. Further, hypoxia initiates a shift of ROR1-positive melanomas to a more invasive, ROR2-positive phenotype. Notably, this receptor switch induces a 10-fold decrease in sensitivity to BRAF inhibitors. In melanoma patients treated with the BRAF inhibitor, Vemurafenib, Wnt5A expression correlates with clinical response and therapy resistance. These data highlight the fact that mechanisms that guide metastatic progression may be linked to those that mediate therapy resistance.”
Reuveni H, Flashner-Abramson E, Steiner L, Makedonski L, et al. Cancer Research. May 7, 2013.
“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.”