Mutations in the KRAS gene are often associated with the development of several types of cancer. Researchers, using mice models, revealed that cancers with such mutations may benefit from a triple therapy, radiation combined with two investigational drugs, trametinib and palbociclib. The study, recently published in Clinical Cancer Research, is titled “Coadministration of Trametinib and Palbociclib Radiosensitizes KRAS-Mutant Non–Small Cell Lung Cancers In Vitro and In Vivo.”
Non-small-cell lung cancer (NSCLC), the most common form of lung cancer (representing nearly 85% of all lung cancer cases), has recently seen major therapeutic advances in some specific genetic subtypes (for instance, in NSCLC harboring mutations in the ALK or EFFR genes), while other subtypes still lack an effective treatment. Particularly, NSCLC harboring KRAS mutations remain resistant to standard and targeted treatments.
Due to this unmet medical need, Dr. Bo Lu, a professor of Radiation Oncology at Thomas Jefferson University, and colleagues analyzed the KRAS-mutant subtype in NSCLC cells. The team found that some cells were more resistant to a drug targeting the KRAS gene pathway than others, and this difference could be caused by a protein called p16. The researchers reached this conclusion after scanning a lung-cancer patients’ genotype database, and finding that patients carrying p16 mutations had a lower overall survival rate in comparison to those without such mutations.
To make the KRAS mutations less resistant to therapy, the team combined the KRAS-targeting drug trametinib with palbociclib. The combination succeeded in making the resistant cancer cells susceptible to radiation treatment. Dr. Lu, the study’s senior author, said in a press release: “If you hit one target another can take over. If you hit two, it becomes a lethal bullet.”
Dr. Lu added: “Currently there is a clinical trial underway to evaluate the combination of two cancer drugs, trametinib and palbociclib, made by two pharma companies for patients with solid tumors and melanoma. Although further research in human subjects is needed to confirm the finding, our study suggests that we may be able to identify non-small-cell lung cancer patients who are likely to benefit most from this combination of therapies.”
To date, neither trametinib nor palbociclib – drugs targeting the KRAS gene mutations and proteins in the p16 pathway – have yet been approved for the treatment of lung cancer, but Dr. Lu hopes this study will contribute to help identify patients who might benefit from this triple therapy approach.