The gist: Oncologists can sometimes test a tumor biopsy from a patient to see if the tumor has certain mutations that can be targeted by specific drugs. New research has uncovered a tumor mutation—deletion of the gene DIXDC1—that could play a role in treatment decisions for people with non-small cell lung cancer (NSCLC). Patients with DIXDC1 deletion or deletion of another gene called LKB1 might benefit from drugs known as FAK inhibitors. (Both DIXDC1 and LKB1 play a role in suppressing metastasis, so when they are missing, it may be easier for lung cancer tumors to spread to other parts of the body.) Further research is needed to investigate whether DIXDC1 and LKB1 deletion could be used to help with treatment decisions.”
“Scientists at the Salk Institute have identified a gene responsible for stopping the movement of cancer from the lungs to other parts of the body, indicating a new way to fight one of the world’s deadliest cancers.
“By identifying the cause of this metastasis—which often happens quickly in lung cancer and results in a bleak survival rate—Salk scientists are able to explain why some tumors are more prone to spreading than others. The newly discovered pathway, detailed today in Molecular Cell, may also help researchers understand and treat the spread of melanoma and cervical cancers.
” ‘Lung cancer, even when it’s discovered early, is often able to metastasize almost immediately and take hold throughout the body,’ says Reuben J. Shaw, Salk professor of molecular and cell biology and a Howard Hughes Medical Institute early career scientist. ‘The reason behind why some tumors do that and others don’t has not been very well understood. Now, through this work, we are beginning to understand why some subsets of lung cancer are so invasive.’ “
“Only 15% of patients with squamous cell lung cancer – the second most common lung cancer – survive five years past diagnosis. Little is understood about how the deadly disease arises, preventing development of targeted therapies that could serve as a second line of defense once standard chemotherapy regimens fail.
“Published online in Cell Reports on June 19, Huntsman Cancer Institute investigators report that misregulation of two genes, sox2 and lkb1, drives squamous cell lung cancer in mice. The discovery uncovers new treatment strategies, and provides a clinically relevant mouse model in which to test them.”
Editor’s note: Some tumors have specific genetic mutations that can allow them to be treated with drugs known as targeted therapies. Studying mice with squamous cell lung cancer tumors, scientists have now discovered two new tumor mutations that open up the possibility for new drugs to be developed for humans. The mutations also indicate that some drugs that already exist for other cancers may be used to treat people with squamous cell lung cancer. More investigation is required before the results of these findings might translate to treatments for patients.
Kim HS, Mendiratta S, Kim J, Pecot CV, et al. Cell. Oct 24, 2013.
We have applied parallel screening of chemical and genetic perturbations within a panel of molecularly annotated NSCLC lines to identify intervention opportunities tightly linked to molecular response indicators predictive of target sensitivity. Anchoring this analysis on a matched tumor/normal cell model from a lung adenocarcinoma patient identified three distinct target/response-indicator pairings that are represented with significant frequencies (6%16%) in the patient population. These include NLRP3 mutation/inflammasome activation-dependent FLIP addiction, co-occurring KRAS and LKB1 mutation-driven COPI addiction, and selective sensitivity to a synthetic indolotriazine that is specified by a seven-gene expression signature.
Metformin is a drug frequently prescribed to treat diabetes, particularly for overweight patients. It works by curbing glucose production in the liver. Metformin is an older drug that was originally developed in the 1920s, but it was abandoned for many years because the clinical focus shifted to insulin for diabetes treatment. However, the drug later made a comeback, and now metformin is the most frequently prescribed drug for type II diabetes. Continue reading…
Liu Y, Marks K, Cowley GS, Carretero J, et al. Cancer Discov. May 28, 2013.
We employed an integrative approach to define novel therapeutic targets in KRAS-driven LKB1 mutant lung cancers. LKB1 mutant lung cancers have deficits in nucleotide metabolism conferring hypersensitivity to DTYMK inhibition, suggesting that DTYMK, encoding deoxythymidylate kinase which catalyzes dTTP biosynthesis, is a potential therapeutic target in this aggressive subset of tumors.
Shackelford DB, Abt E ... Mischel PS, Shaw RJ. Cancer Cell. Jan 24, 2013
“The LKB1 (also called STK11) tumor suppressor is mutationally inactivated in ∼20% of non-small cell lung cancers (NSCLC). LKB1 is the major upstream kinase activating the energy-sensing kinase AMPK, making LKB1-deficient cells unable to appropriately sense metabolic stress. We tested the therapeutic potential of metabolic drugs in NSCLC and identified phenformin, a mitochondrial inhibitor and analog of the diabetes therapeutic metformin, as selectively inducing apoptosis in LKB1-deficient NSCLC cells. Therapeutic trials in Kras-dependent mouse models of NSCLC revealed that tumors with Kras and Lkb1 mutations, but not those with Kras and p53 mutations, showed selective response to phenformin as a single agent, resulting in prolonged survival. This study suggests phenformin as a cancer metabolism-based therapeutic to selectively target LKB1-deficient tumors.”