Researchers at the University of California Los Angeles (UCLA) report that continuous dosing with MAP kinase (MAPK)-targeted inhibitors may not be in the best interest of melanoma patients. They theorize that patients may benefit from a holiday from MAPK inhibitors while alternative therapies stave off emergence of resistant melanoma clones. In a study published online ahead of print in Cancer Discovery, they report on some of the mechanisms by which treatment-resistant melanoma may become vulnerable to a drug holiday from MAPK-targeted inhibitors.
The researchers analyzed the cellular responses of treatment-resistant melanoma, both before and after withdrawal from MAPK therapy. “We found that melanoma resistant to MAPK pathway inhibitors develop addiction to these drugs. Addiction in this context means that acute withdrawal of MAPK inhibitors would reduce fitness of the tumor cells,” said study investigator Roger Lo, MD, professor of medicine (dermatology) and molecular and medical pharmacology at the David Geffen School of Medicine at UCLA.
He said the team was surprised to find that this reduction in tumor cell fitness in many cases was transient. It appeared to be caused by tumor cells that initially slowed their proliferation and then later resumed fast proliferation. Dr. Lo said in other cases the majority of tumor cells underwent cell death upon MAPK inhibitor withdrawal.
The findings were demonstrated in several major subtypes of melanoma tumors including BRAF and NRAS melanoma. It is hoped this will lead to new therapeutic strategies that suppress the development of drug resistance in melanoma patients. Approximately 50% of advanced melanoma tumors are driven by BRAF mutations and another 20% by NRAS mutations. While MAPK-targeted inhibitors, such as BRAF and MEK inhibitors selectively block key cancer-driving signals, resistance occurs.
Dr. Lo said state-of-the-art technology has ushered in the ability to investigate the molecular differences underlying the distinct drug addiction phenotypes in melanoma patients. “We further found that the reason certain drug-resistant melanoma cells die rather than slow their proliferation transiently is that pERK levels accumulate to extremely high levels—levels that induced DNA damage,” Dr. Lo told OncoTherapy Network.
These new findings suggest that DNA damage repair inhibitors, which are used to treat some gynecologic malignancies, may be useful against treatment-resistant melanoma. Dr. Lo said it is hoped that further studies will elucidate optimal strategies for intermittent MAPK inhibitor therapy and rotational therapy with agents that hit targets unique to MAPK inhibitor-resistant tumors.
“We were also surprised to find that NRAS mutant melanoma can develop resistance and strong addiction to a single agent, the MEK inhibitor trametinib. Thus, we found a potentially new strategy to pharmacologically select against melanoma as they develop resistance to MAPK inhibitors,” said Dr. Lo.