Devastating to patients and frustrating for doctors, resistance to treatment is all too common in many types of cancers. A patient may respond positively to treatment for weeks, months or more than a year, and then hit a wall where the treatment is no longer working as well or the tumor begins to grow again. "At first, the tumor just melts away," says Arturo Loaiza-Bonilla, MD, MSEd, FACP, Chief of Medical Oncology and Medical Director of Research at our hospital in Philadelphia. "But once you get to a core of cells that don't budge, you know those cells are resistant and those cells are going to start to grow. It's very frustrating."
“ Once you get to a core of cells that don't budge, you know those cells are resistant and those cells are going to start to grow. It's very frustrating.” - Arturo Loaiza-Bonilla, MD, MSEd, FACP
A tumor may be resistant to treatment for many reasons. In some cases, the tumor’s makeup has always contained resistant cancer cells, but they went undetected, even with a genomic test or pathology exam. But in other cases, the cancer adapts by developing new mutations or reproducing protective genes, either as part of its natural evolution or as a reaction to ongoing treatment.
When cancer's driver mutation changes
Picture cancer as a bus barreling down the road with few obstacles ahead. Over time, it picks up new cells along the way and finds ways to refuel itself. "You have a driver mutation that's driving that bus," says Ashish Sangal, MD, Medical Oncologist and Medical Director of the CTCA® Lung Cancer Center at our hospital near Phoenix. The driver mutation is the dominant genetic feature in the cells of that tumor, allowing it to thrive. By identifying that driver, doctors may be able to match a cancer drug that targets specific mutations. "We have to identify the driver and target that driver. Eventually, it loses control, lets up on the gas, and sometimes, the bus shuts down." Other times, one of the passengers takes over and a new driver allows the tumor to survive and grow. "That's where the cancer has adapted, and you have to try something new," Dr. Sangal says.
When mutations develop mutations
Healthy cells rely on several genes to help regulate growth and division, among them the epidermal growth factor receptor (EGFR). But when that gene mutates, it may lead to uncontrolled cell growth that causes tumors to form. Some cancers with an EGFR mutation may respond to targeted therapy drugs such as erlotinib (Tarceva®), afatinib (Gilotrif®) or gefitinib (Iressa®) for several months before resistance kicks in. "We have seen a second mutation develop that is actually protecting the original EGFR mutation," Dr. Sangal says. "So even if we continue targeting the primary receptor, this new mutation is blocking it." That mutation may be targeted with the drug osimertinib (Tagrisso®). "That's the counterpunch,” Dr. Sangal says, adding that that mutation may also become resistant to treatment over time.
When the drug never reaches the cancer cells
Researchers are learning more about proteins known as drug transporters, enzymes that carry drugs into and out of cells. One particular transporter of interest is a substance called P-glycoprotein (P-gp), described in a National Cancer Institute article as a "garbage chute that pumps waste, foreign particles, and toxins out of cells." P-gp is meant to protect cells from toxins, but researchers have also determined that they may flush out chemotherapy drugs that are considered lethal to cells. P-gp is a member of the multidrug resistance (MDR) gene family. In a process called gene amplification, researchers believe some cancer cells may produce hundreds of MDR genes that overwhelm drug treatments and prevent them from working. Some researchers theorize that developing drugs that inhibit P-gp may allow treatments to remain inside cells longer, giving them more time to work.
Undaunted, doctors and researchers are constantly looking for new ways to combat cancer's resistance to treatment drugs. Ongoing research is studying potential new therapies designed to attack genetic features that are not yet targeted by existing drugs. Drug combinations have shown to be another option in attacking multiple targets simultaneously or in succession. "We're hitting cancer from many different sides," Dr. Sangal says. "That’s where clinical trials come into play. We are treating cancer with what we have, but what can we add to that treatment to get the best results?"