A new UC San Francisco–led study challenges the dogma in oncology that most cancers are caused by one dominant "driver" mutation that can be treated in isolation with a single targeted drug. Instead, the new research finds one of the world's most deadly forms of lung cancer is driven by changes in multiple different genes, which appear to work together to drive cancer progression and to allow tumors to evade targeted therapy.
These findings -; published online on November 6, 2017 in Nature Genetics -; strongly suggest that new first-line combination therapies are needed that can treat the full array of mutations contributing to a patient's cancer and prevent drug resistance from arising.
"Currently we treat patients as if different oncogene mutations are mutually exclusive. If you have an EGFR mutation we treat you with one class of drugs, and if you have a KRAS mutation we pick a different class of drugs. Now we see such mutations regularly coexist, and so we need to adapt our approach to treatment," said Trever Bivona, MD, PhD, a UCSF Medical Center oncologist, associate professor in hematology and oncology, and member of the Helen Diller Family Comprehensive Cancer Center at UCSF.
Lung cancer is by far the leading cause of cancer death worldwide. Efforts to identify the genetic mutations that drive the disease have led to targeted treatments that improve life expectancy for many patients, but these drugs produce temporary remission at best -; sooner or later, cancers inevitably develop drug resistance and return, deadlier than ever.
The new UCSF-led study -; which analyzed tumor DNA from more than 2,000 patients in collaboration with Redwood City–based Guardant Health -; is the first to extensively profile the genetic landscape of advanced-stage non–small cell (NSC) lung cancer, the most common form of the disease.
"The field has been so focused on treating the 'driver' mutation controlling a tumor's growth that many assumed that drug-resistance had to evolve from new mutations in that same oncogene. Now we see that there are many different genetic routes a tumor can take to develop resistance to treatment," said Bivona, who is also co-director of a new UCSF-Stanford Cancer Drug Resistance and Sensitivity Center funded by the National Cancer Institute. "This could also explain why many tumors are already drug-resistant when treatment is first applied."