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When chemotherapy stops working

Multidrug resistance is a common culprit

Dec 09, 2019

by Anirban Datta

Over 100 million people worldwide have cancer and odds are that over a third of us will get a cancer diagnosis during our lifetime. Thanks to advances in early detection and treatment, five-year cancer survival rates increased from 50% to 67% between the 1970s and 2010s. With new treatments like immunotherapy and targeted therapy added to the oncologist’s arsenal, the outlook for patients is steadily improving.

The mainstay of cancer therapy, however, remains chemotherapy, a class of treatments that—perhaps surprisingly--has its origins in war. During World War II, scientists noticed that people who had been exposed to weaponized mustard gas showed reduced white blood cell counts. Launching from there, researchers discovered that nitrogen mustard, a derivative of mustard gas, was able to stop cancer cells’ usually rapid division.

By the late 1940s, physicians had successfully integrated nitrogen mustard and other products of mustard gas into the treatment of lymphomas. Even today, some forms of this first-generation chemotherapy are used to treat certain lymphomas and breast cancers. Over the following decades, more and more researchers began exploring chemicals that block DNA synthesis, replication, and cellular metabolism or division, like folate analogues and plant alkaloids, developing the fundamentals for fighting a range of tumors.

From the onset, chemotherapy was integrated with other forms of cancer treatment such as radiation and surgery, and chemo as either a primary or adjuvant part of cancer care was born. Today, about 10 million new cancer patients receive chemotherapy per year.

Typically, chemotherapy is administered in multiple cycles of 2–6 weeks each. As with many prescription medications, cancer patients relying on chemotherapy are often faced with a major problem: after long-term use, chemo medications can become ineffective, a process called drug resistance.

Cancer cells find many different ways to resist treatment. One common mechanism is to pump drugs out of the tumor cells before they have a chance to work. The flow of molecules into and out of a cell is a delicate balance that is maintained by transport proteins, or transporters for short. Think of these as mechanized gateways that maintain the balance of what should and shouldn’t be inside a cell.

When toxins enter a cell, transporters go into overdrive to pump the toxins out of the cell. Considering that chemotherapies are inherently toxins—they are designed to kill cells by diffusing in and disrupting their lifecycle—it’s hardly surprising that transporters on tumor cells would try to adapt and pump out chemo agents as quickly as they can. If the transporter succeeds and expels the drug molecules, the medicine is rendered ineffective. Over the course of a chemotherapy cycle, mostly those cells with transporters that can ramp up their activity fast enough will survive, and the tumor becomes resistant to the drug.

Doctors attempt to use combination chemotherapy, administering two or more chemo drugs at the same time, to lessen the likelihood of resistance. The idea of this approach is to overwhelm the cancer cells with several different types of chemo medications. Ideally, this leaves the cells unable to pump out all of the toxins, aka drugs, before they have had a chance to take hold in the cell.

Although this approach often succeeds in making chemotherapy work for longer periods of time, many cancer cells still eventually become resistant to the drug combinations. As a result, doctors are careful to monitor progress and pre-empt resistance before cells can fully adapt by switching to a new cocktail of chemo agents.

Combination therapy has been effective for millions of cancer patients, but still, far too many patients struggle with drug resistance. There’s ample reason for pharmaceutical companies and academic researchers to study the underlying mechanisms of drug resistance and to work toward a new generation of chemotherapy agents that are less prone to drug resistance.

Anirban Datta is Senior Director of Discovery Biology at Verseon.


- cancer - chemotherapy -