Could Cytostatic Drugs Unleash Antitumor Immunity in Lung Cancer?

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The combination of trametinib and palbociclib induced attack by NK cells — but not killing — of xenograft lung tumors in lab animals.
The combination of trametinib and palbociclib induced attack by NK cells — but not killing — of xenograft lung tumors in lab animals.

From chemotherapy and radiotherapy to targeted gene therapies, the overriding goal of cytotoxic cancer therapies is to obliterate or shrink tumors. But researchers are now exploring how treatment-induced tumor-cell senescence (a cell state associated with permanent halts in cell division and growth, induced by DNA damage) with cytostatic drugs can halt cellular division and tumor progression. This approach potentially prolongs patients' lives, even though it may not actually kill malignant cells. 

By combining 2 tumor cell-division–signaling pathway inhibitors, the MEK inhibitor trametinib and the CDK4/6 inhibitor palbociclib, researchers at the Sloan Kettering Cancer Center, New York, New York, reported in Science that it is possible to shrink lung adenocarcinomas without killing tumors outright, prolonging animal survival in preclinical mouse experiments.1,2 The combination was particularly effective against KRAS-mutation–positive tumors.1

“Cancer drugs that merely halt the proliferation of cancer cells have not been widely pursued, owing to the fact that we generally want tumors to shrink,” noted study coauthor Scott W. Lowe, PhD, Chair of the Cancer Biology and Genetics Program at Memorial Sloan Kettering Cancer Center's Sloan Kettering Institute (SKI), in a SKI press release.3

But with the development of anticancer immunotherapies, it has become clear that when tumor cells become senescent, and are no longer actively dividing, natural killer (NK) immune cells will frequently attack tumors. In patient tumor cell-line and tumor tissue experiments, and through the use of KRAS-mutation–positive lung adenocarcinoma tumor-xenograft mice, Dr Lowe and colleagues showed that using trametinib and palbociclib in combination blocks cellular division signals and triggers tumor-shrinking immunity, prolonging survival times of mice.1 

But when the researchers replicated their xenograft experiments with immunocompromised mice, the cytostatic regimen lost its efficacy — providing strong evidence that the benefits of induced tumor-cell senescence are mediated by immune attack.1 The combination promoted retinoblastoma [RB] protein-mediated cellular senescence, triggering immune attack, the authors concluded.1 

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