Combined MEK, BRAF Inhibitors Promising in Melanoma

The gist: Researchers have conducted a clinical trial with volunteer patients to test a new melanoma treatment that combines the drugs cobimetinib and vemurafenib. The participants all had melanoma tumors with BRAFV600 mutations. People with BRAFV600 mutations often become resistant to treatment if they take a “BRAF inhibitor” like vemurafenib. The hope is that drugs like cobimetinib can be given alongside vemurafenib to circumvent resistance. The researchers found that the combination treatment was safe for these patients, and there was some promising evidence that the treatment was effective, but more follow-up will be needed.

“Combined treatment of BRAFV600-mutated melanoma with the MEK inhibitor cobimetinib and the BRAF inhibitor vemurafenib was safe and tolerable, according to the results of a phase Ib study.

“Based on the promising antitumor activity seen with the combination, researchers led by Antoni Ribas, MD, of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, and colleagues recommended further clinical development and testing of this combination.

“According to background information published with the study in Lancet Oncology, patients with BRAFV600-mutated metastatic melanoma often develop resistance to treatment with a BRAF inhibitor, ‘which frequently reactivates the MAPK pathway through MEK.’ Prior research has shown that sequential treatment with a MEK inhibitor after this progression does not result in meaningful antitumor activity.”

Scientists Find New Way to Combat Drug Resistance in Skin Cancer

“Rapid resistance to vemurafenib – a treatment for a type of advanced melanoma, the deadliest form of skin cancer – could be prevented by blocking a druggable family of proteins, according to research published in Nature Communications today.

“Scientists at the Cancer Research UK Manchester Institute, based at the University of Manchester, have revealed the MLK family of four enzymes ‘undoes’ the tumour-shrinking effects of vemurafenib.”

Editor’s note: This story describes a potential new way to treat melanoma that has become resistant to vemurafenib. While promising, the research is still in preliminary stages, so new treatments are not yet available for patients.

Overcoming Resistance to BRAF Inhibitors May Take Two More Drugs

We already knew that melanomas can resist BRAF inhibitor drugs by activating a particular cancer pathway (a group of proteins in a cell that work together to control cell multiplication, which can lead to tumor growth)—but new research shows that this resistance can also be caused by activating a second cancer pathway. The first pathway is called MAPK and the second is called PI3K-PTEN-AKT. The researchers studied 100 melanomas that resisted the BRAF inhibitors vemurafenib or dabrafenib, and found that 70% had mutations in the first pathway, while 22% had mutations in the second pathway. Moreover, mutations in both pathways could occur in the same tumor, suggesting that thwarting resistance to BRAF inhibitors may require targeting both pathways with a combination treatment.

Identification of Multiple Mechanisms of Resistance to Vemurafenib in a Patient with BRAFV600E-Mutated Cutaneous Melanoma Successfully Rechallenged After Progression

“Purpose: To investigate the mechanism(s) of resistance to the RAF-inhibitor vemurafenib, we performed a comprehensive analysis of the genetic alterations occurring in metastatic lesions from a patient with a BRAFV600E-mutant cutaneous melanoma who, after a first response, underwent subsequent rechallenge with this drug. Experimental Design: We obtained blood and tissue samples from a patient diagnosed with a BRAFV600E-mutant cutaneous melanoma that was treated with vemurafenib and achieved a near-complete response. At progression, he received additional lines of chemo/immunotherapy and was successfully re-challenged with vemurafenib. Exome and RNA sequencing were performed on a pre-treatment tumor and two subcutaneous resistant metastases, one that was present at baseline and previously responded to vemurafenib (PV1), and one that appeared de novo after reintroduction of the drug (PV2). A culture established from PV1 was also analyzed…Conclusions: This work describes the co-existence within the same patient of different molecular mechanisms of resistance to vemurafenib affecting different metastatic sites. These findings have direct implications for the clinical management of BRAF-mutant melanoma.”

Therapeutic Destruction of Insulin Receptor Substrates for Cancer Treatment

“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.”

First Evidence That Taking Breaks from Treatment May Prevent Vemurafenib Resistance in People

The drug vemurafenib targets melanomas with BRAF mutations, but treatment usually stops working after just 6 to 8 months because tumors become drug-resistant. However, resistance could be avoided by giving people periodic breaks from treatment, suggests work presented at the 2013 meeting of the American Association for Cancer Research. The researchers found that stopping treatment slowed tumor growth in 14 out of 19 people with vemurafenib-resistant melanomas. They also found that intermittent treatment (4 weeks on and 2 weeks off) prevented vemurafenib resistance in human melanomas implanted in mice. This strengthens the researchers’ previous work showing that vemurafenib-resistant melanomas actually depend on the drug to grow.

Targeting Non-BRAF Mutations in Melanoma to Address BRAF Inhibitor Therapy Resistance

BRAF-mutated metastatic melanoma can be treated with the U.S. Food and Drug Administration (FDA)-approved drug vemurafenib, an oral therapy that targets the V600E mutation in the BRAF protein. Another BRAF inhibitor, dabrafenib, has been filed with the FDA for treatment of the same patient population. BRAF inhibition results in rapid shrinkage of tumors for the majority of BRAF-mutated melanoma patients. But while treatment with a BRAF inhibitor alone results in tumor shrinkage in the short-term, patients’ tumors begin to grow again, typically 6 to 7 months after starting treatment. Continue reading…

Pharmacodynamic Effects and Mechanisms of Resistance to Vemurafenib in Patients With Metastatic Melanoma

PURPOSE: To assess pharmacodynamic effects and intrinsic and acquired resistance mechanisms of the BRAF inhibitor vemurafenib in BRAFV600-mutant melanoma, leading to an understanding of the mechanism of action of vemurafenib and ultimately to optimization of metastatic melanoma therapy…”

Dabrafenib Bests Chemotherapy and May be Safer than Vemurafenib

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.