Pew-Stewart Scholars Explore Intricacies of Drug Resistance in Lung Cancer

Lung cancer is one of the most pervasive and deadliest forms of cancer in the United States. Despite continued strides by scientists to better prevent, identify, and treat the disease, the American Cancer Society estimates that there will be more than 235,000 new cases and 130,000 deaths from lung cancer in 2021 alone.

Early signs of lung cancer, such as breathlessness or coughing, are easy to overlook, which can result in later diagnosis and a poorer prognosis. Once identified, the disease is often too advanced to be cured through treatments or surgery, with therapies able to only prolong a patient’s survival.

Many Pew-Stewart scholars—early-career scientists whose main research focus is to advance our understanding of cancer—have dedicated new efforts to investigating the mechanisms of drug resistance in lung cancer. This November, in recognition of Lung Cancer Awareness Month, we highlight two researchers working to uncover promising new treatments for this deadly disease.

How lung cancers become resistant to therapy

Most lung cancer patients are diagnosed with non-small cell lung cancer (NSCLC). Nearly a quarter of these cases can be traced back to a specific gene mutation called KRAS G12C, which codes for a mutant form of the KRAS protein.

KRAS operates within a signaling pathway that tells cells when to divide or take on specialized roles. It oscillates between an active and inactive state, but when mutated, the protein remains mostly “on” and can signal cancer cells to continue multiplying uncontrollably.

This protein takes center stage in 2019 Pew-Stewart scholar Piro Lito’s lab, where his team uses biochemical and genetic approaches to study the properties of KRAS mutations in order to develop drugs that target cancers with these mutations more effectively.

Lito’s previous work described a pharmaceutical drug that is able to “trap” mutant KRAS proteins in their inactive state, putting the brakes on cell division and growth. The drug is now FDA-approved, making it the first KRAS inhibitor to receive this green light. Although it was shown to be effective in slowing the progression of lung cancer in some patients who had already received other treatment, other patients developed resistance—meaning the pharmaceutical therapy stopped working.

To understand what causes such resistance, Lito’s lab began to investigate the genetic differences between pre- and post-treatment tumors. In recent findings reported in the journal Nature, the team uncovered alterations in multiple genes in tumors that were not present before treatment, indicating that they may have emerged in response to therapy. These changes allowed cancer cells to bypass the drug’s effect on KRAS and begin dividing again.

By identifying these genetic variants, scientists may be able to study new treatment options such as combination therapy or other targeted therapies for patients with additional mutations. Lito’s group is looking to learn whether the use of other drugs could improve the longevity of KRAS inhibitors and prolong a patient’s response to it.

Why immune cells fail to respond to immunotherapy

The immune system is critical in leading the body’s attack against disease and infection. This complex system can also be directed toward specific cancer-fighting purposes through a form of immunotherapy known as immune checkpoint blockade (ICB).

Immune checkpoints are a part of the body’s natural immune response and can prevent T-cells from overattacking and destroying healthy cells. However, in cancer, these same checkpoints can also hinder T-cells’ ability to attack tumors efficiently. ICB can be used to invigorate and stimulate T-cells to mount an uninhibited assault on cancer cells. This form of immune therapy was first approved to treat lung cancer in 2015. Although this therapy can help improve survival and control tumor growth, resistance can still develop. Stefani Spranger, a 2019 Pew-Stewart scholar, is exploring the immune system for answers behind why only a subset of patients with NSCLC respond to ICB.

Previously, researchers thought that resistance to ICB resulted from T-cells becoming overstimulated or “exhausted” from targeting cancer cells. Spranger’s lab instead linked ICB resistance problems to gene activation differences between responsive and nonresponsive T-cells. This occurs in the lymph node, when T-cells assume their roles prior to becoming activated to fight cancer. Using a mouse model of NSCLC, the team noticed that nonresponsive T-cells made lower levels of receptors for cytokines, which were critical to their immune function and activation.

The team then determined that by administering cytokines, the immune system’s signaling molecules, the function of these nonresponsive T-cells could be reversed.

Spranger’s work, which was published in the journal Science Immunology, revealed that T-cell dysfunction is a preset condition, providing new information for scientists developing innovative strategies to improve the use of immunotherapy for lung cancer treatment.

Kara Coleman is the director of The Pew Charitable Trusts’ biomedical programs, including the biomedical scholars, Pew-Stewart Scholars for Cancer Research, and Latin American fellows programs, and Jennifer Villa is an officer supporting the programs.