Resistance to targeted cancer therapies may be almost inevitable, at least if they are used alone, two groups of researchers reported online in Nature.
Mathematical modeling, based on genetic testing of colorectal cancer patients, suggests that resistance already exists even before targeted therapy begins, according to Luis Diaz, MD, of Johns Hopkins Kimmel Cancer Center, and colleagues.
One effect of single-agent targeted therapy, they noted, is to allow tumor cells containing resistance mutations to grow and prosper, leading to disease progression.
A second group, led by Alberto Bardelli, PhD, of the Institute for Cancer Research and Treatment in Turin, Italy, found some evidence of preexisting resistance, but added that resistance could also emerge as a result of single-agent targeted treatment.
The solution, both groups argued, may be to use combination therapies to delay or prevent progression.
Molecules that block the epidermal growth factor receptor (EGFR) often have a dramatic initial effect on cancers driven by the receptor, Diaz and colleagues noted.
But resistance almost always arises within a few months of starting therapy, leading to relapse, although the exact mechanisms of the resistance have been unclear.
To help clarify the situation, they studied 28 patients with metastatic colorectal cancer, a disease in which patients whose tumors have a wild-type KRAS gene are often sensitive to EGFR blockade.
Four of the patients already had KRAS mutations at the start of monotherapy with panitumumab (Vectibix), a monoclonal antibody aimed at EGFR. But nine of the remaining 24 with normal KRAS developed mutations about 5 or 6 months after starting treatment.
Mathematical modeling, Diaz and colleagues wrote, showed that the parent cells of those with KRAS mutations must have been present before the panitumumab treatment started.
“These resistance mutations develop by chance as cancer cells divide so that tumors always contain thousands of resistance cells,” Diaz said in a statement, adding that the findings likely apply to any targeted cancer therapy.
Co-author Bert Vogelstein, MD, also of Johns Hopkins, added that the finding means that “long-term remissions of advanced cancers will be nearly impossible with single targeted agents.”
The research team also noted that their method – testing tumor DNA found in the blood – is noninvasive and was able to detect changes in KRAS long before those changes translated into renewed tumor growth.
That should allow physicians the opportunity to alter the treatment, perhaps by adding agents to the regimen.
“The good news is that there is a limited number of pathways that go awry in cancer, so it should be possible to develop a small number of agents that can be used in a large number of patients,” Vogelstein said in a statement.
Bardelli and colleagues reached similar conclusions after studying colorectal tumor cell lines and a group of 10 patients with metastatic disease who were being treated with cetuximab (Erbitux), a chimeric antibody aimed at EGFR.
They found that preexisting KRAS mutations were amplified in one patient and emerged after treatment in six others.
The resistance mutations were detectable in blood samples as early as 10 months before radiological assessment confirmed that the disease had progressed, Bardelli and colleagues said.
“Our results suggest that blood-based noninvasive monitoring of patients undergoing treatment with anti-EGFR therapies … could allow for the early initiation of combination therapies that may delay or prevent disease progression,” they concluded.
The study by Diaz and colleagues was supported by The Virginia and D. K. Ludwig Fund for Cancer Research, the National Colorectal Cancer Research Alliance, the NIH, the National Cancer Institute, the European Research Council, the Austrian Science Fund, and the John Templeton Foundation.
The authors declared competing financial interests, including affiliations with Personal Genome Diagnostics and Inostics.
The study by Bardelli and colleagues had support from the European Union Seventh Framework Programme, the Associazione Italiana per la Ricerca sul Cancro, the Regione Piemonte, the Fondazione Piemontese per la Ricerca sul Cancro, Oncologia Ca’ Granda ONLUS, Mr William H. Goodwin and Mrs Alice Goodwin and the Commonwealth Foundation for Cancer Research, the Experimental Therapeutics Center of Memorial Sloan-Kettering Cancer Center, the Society of MSKCC, the NIH, the Beene Foundation, and the Regione Lombardia and Ministerio Salute.
The authors declared they had no competing financial interests
