Two-drug approach halts lung tumors by starving them metabolically

(Illustration: Fawn Gracey)

Non-small-cell lung cancer is the leading cause of cancer death in the U.S. Roughly 1 in 4 cases are driven by the mutant KRAS oncogene. Though scientists have tried for more than three decades to target KRAS with drugs, they’ve had little success.

In a new study led by Nada Kalaany, PhD, and colleagues at Boston Children’s Hospital took a different approach, looking at what these deadly lung tumors need metabolically to live and grow. Reporting in the Proceedings of the National Academy of Sciences (PNAS), they show that a combination of two existing drugs can effectively starve tumors in a mouse model.

Targeting a growth pathway in non-small-cell lung cancer

Unable to effectively target the KRAS oncogene itself, scientists have turned to related biological pathways. One pathway involves insulin and insulin-like growth factor-1 (IGF-1), which influence the uptake and release of nutrients and, ultimately, cell growth. But this pathway hasn’t been proven definitively to fuel KRAS-driven lung cancers, and inhibitors of IGF-1 signaling have so far failed in clinical trials. A recent study in mice saw lung tumors become more aggressive. But this study targeted insulin/IGF-1 signaling only partially.

Our work tries to identify metabolic dependencies and vulnerabilities in tumors.In the new work, Kalaany and colleagues used genetic techniques to completely block insulin/IGF-1 signaling. They used a new mouse model, the best test ground yet for studying the pathway’s role in KRAS-driven lung cancer. Their findings establish that fully blocking insulin/IGF-1 signaling can slow tumor growth — but also show that a second step is needed.

The work is also a great example of how cancer insights can sometimes come from outside oncology – in this case, an endocrinology lab.

A new model of growth factors’ effect in lung tumors

To create the new model, Kalaany’s team crossed two strains of mice: a well-established strain that models KRAS-driven lung cancer, and another strain that lacks insulin/IGF-1 signaling. This second strain, previously developed by Morris White, PhD to study diabetes, deletes the genes Irs1 and Irs2. These genes encode so-called “adaptor” proteins, which White (a co-author on the paper) identified decades ago as being necessary for insulin/IGF-1 signaling.

When the researchers deleted both Irs1 and Irs2 in the lungs of these cross-bred mice, insulin/IGF-1 signaling was eliminated and lung tumors were strongly suppressed, as shown here:

Credit: Clare (He) Xu, PhD, Boston Children’s Hospital

“Almost all animals in this lung cancer model typically die within 15 weeks of KRAS activation,” says Kalaany, who is also an assistant professor at Harvard Medical School and an associate member of the Broad institute of MIT and Harvard. “But the ones that lost both Irs1 and Irs2 were completely fine – we saw almost no tumors at 10 to 15 weeks.”

Blocking a tumor workaround

Kalaany and her colleagues were excited by this result, since IGF-1 inhibitor drugs are already available and block insulin/IGF-1 signaling as effectively as Irs1/2 deletion.

But they also knew that tumor cells often figure out work-arounds.

“We decided to let the animals live longer, and sure enough, at around 16 weeks we started seeing some tumors,” says Kalaany. “So then we asked, how were these tumor cells able to overcome loss of Irs1 and Irs2?”

Metabolic profiling revealed that tumor cells from the Kras-mutant mice lacking Irs1/2 had significantly lower levels of essential amino acids, the building blocks of protein, as this “heat map” of six tumor lines indicates in blue. (Essential amino acids, which must be acquired from the diet, are listed in bold.)

Clare (He) Xu, PhD

Yet just outside the cell, amino acids were plentiful.

“Growth factors like IGF-1 tell cells that nutrients are around, so when you suppress their signaling, the tumor cells don’t take up the amino acids and think they are starved,” Kalaany explains. “But we also found that the tumor cells can compensate for this and break down their own proteins to generate amino acids.”

A metabolic approach to cancer

That’s where the second step comes in. Protein breakdown can also be inhibited with existing drugs, such as chloroquine, which inhibits autophagy (literally, “self-eating”) and is being used in several cancer drug trials, and bortezomib (Velcade), a so-called proteasome inhibitor that is used to treat multiple myeloma.

nitrogen disposal pancreatic cancer

A metabolic approach to pancreatic cancer? In previous work, Kalaany’s lab showed that targeting an enzyme that helps dispose of excess nitrogen curbed malignant growth of pancreatic tumors in obese mice.

When Kalaany and colleagues injected mice with human tumor cells lacking Irs1/2, tumors grew less well than in mice carrying the two genes. When the team added inhibitors of protein breakdown, tumor growth was suppressed almost completely.

Kalaany now proposes that combining IGF-1 inhibitors with inhibitors of protein breakdown could provide an alternative to chemotherapy in curbing KRAS-mutant lung cancer. Though the drugs are well tolerated, care would need to be taken in dosing any combination therapy to avoid toxicities, she says, and such therapies might also be safer if targeted to the lungs.

Like another recent study from Kalaany’s lab on pancreatic cancer, the current study shows how targeting metabolism in cancer cells can be an effective weapon.

“Our work tries to identify metabolic dependencies and vulnerabilities in tumors,” says Kalaany.  “If we identify collaborators, we would love to have a clinical trial in non-small-cell lung cancer combining IGF-1 inhibitors with autophagy inhibitors or proteasome inhibitors.”

The fine print

The study was supported by Boston Children’s Hospital and the NIH/National Cancer Institute (R01 CA211944).

Kalaany was senior author on the paper. He Xu and Min-Sik Lee of Boston Children’s Division of Endocrinology were co-first authors. Other authors were Pei-Yun Tsai, Ashley S. Adler, Natasha L. Curry, Saketh Challa, Kyle D. Copps and Morris F. White of Boston Children’s; Elizaveta Freinkman of the Whitehead Institute for Biomedical Research; Daniel S. Hitchcock and Clary B. Clish of the Broad Institute of MIT and Harvard, Roderick T. Bronson of Tufts University; and Michael Marcotrigiano and Yaotang Wu of Boston Children’s Department of Radiology.