Study of 'Super Responder' Reveals New Oncogene for Lung Cancer

“Researchers have taken the next step in confirming the identity of previously unknown gene mutation that drives lung cancer development. Scientists at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC – James) originally identified the mutation in one patient out of nine with advanced lung cancer who responded well to the drug sorafenib. The clinical trial involved 306 participants total.

“Within two months of beginning treatment, the patient had demonstrated a near complete response, and she remained progression-free and asymptomatic for five years while continuing to take sorafenib by mouth.”

Editor’s note: Different patients’ tumors have different genetic mutations. More and more, doctors are using patients’ tumor genetics to match patients with treatments that are most likely to work for them. Now, researchers have discovered a mutation called S214C, which may help doctors predict some lung cancer patients’ responses to treatment. The mutation was found in a patient in a clinical trial who responded particularly well to a drug called sorafenib.

Prevalence of New Genetic Driver in Lung Cancer Shown in Study

“A line has been drawn from mutation of the gene NTRK1, to its role as an oncogene in non-small cell lung cancer, to treatment that targets this mutation. ‘Everything we know about lung cancer points to the idea that when we find one of these genetic drivers and can target it with a drug, patients will respond and tend to have a good amount of time on drug before it becomes ineffective. Obviously we can’t guarantee the effectiveness of targeting the NTRK1 mutation at this point, but everything we know about these kinds of genes makes us extremely hopeful,’ says one researcher.”

Editor’s note: A new targeted therapy treatment may be on the horizon for some lung cancer patients. Targeted therapies work by targeting specific molecules inside cancer cells. Often, these molecules are proteins that are mutated and cause cancer cells to multiply rapidly, contributing to tumor growth. There are several mutated proteins commonly found in non-small cell lung cancer (NSCLC) tumors. For a given patient, these can be detected by molecular testing, and based on the results, doctors can prescribe certain targeted therapy drugs. A newly discovered mutation called NTRK1 is being explored as a potential target for a new targeted therapy. To test the new drug, called LOXO-101, scientists have started a new clinical trial and are enrolling patients whose tumors have NTRK1 mutations.

Foretinib is a Potent Inhibitor of Oncogenic ROS1 Fusion Proteins

“We demonstrate that foretinib is a more potent ROS1 inhibitor than crizotinib in vitro and in vivo and remains effective against crizotinib-resistant ROS1 kinase domain mutations, including ROS1 G2032R. Taken together, our findings establish foretinib as a highly promising therapeutic candidate for treating patients with ROS1-driven malignancies and provide rationale for rapid clinical translation.”

Zbtb7a Suppresses Prostate Cancer Through Repression of a Sox9-Dependent Pathway for Cellular Senescence Bypass and Tumor Invasion

“Zbtb7a has previously been described as a powerful proto-oncogene. Here we unexpectedly demonstrate that Zbtb7a has a critical oncosuppressive role in the prostate. Prostate-specific inactivation of Zbtb7a leads to a marked acceleration of Pten loss-driven prostate tumorigenesis through bypass of Pten loss-induced cellular senescence (PICS). We show that ZBTB7A physically interacts with SOX9 and functionally antagonizes its transcriptional activity on key target genes such as MIA, which is involved in tumor cell invasion, and H19, a long noncoding RNA precursor for an RB-targeting microRNA.”

MicroRNA-135b Promotes Lung Cancer Metastasis by Regulating Multiple Targets in the Hippo Pathway and LZTS1

“Dysregulation of microRNAs has a critical role in cancer progression. Here we identify an intronic microRNA, miR-135b that is upregulated in highly invasive non-small-cell lung cancer cells. Expression of miR-135b enhances cancer cell invasive and migratory abilities in vitro and promotes cancer metastasis in vivo, while specific inhibition of miR-135b by a miR-135b-specific molecular sponge and antagomirs suppresses cancer cell invasion, orthotopic lung tumour growth and metastasis in a mouse model.”

Small Molecule Inhibition of the KRAS–PDEδ Interaction Impairs Oncogenic KRAS Signalling

“The KRAS oncogene product is considered a major target in anticancer drug discovery123. However, direct interference with KRAS signalling has not yet led to clinically useful drugs34567,8. Correct localization and signalling by farnesylated KRAS is regulated by the prenyl-binding protein PDEδ, which sustains the spatial organization of KRAS by facilitating its diffusion in the cytoplasm91011. Here we report that interfering with binding of mammalian PDEδ to KRAS by means of small molecules provides a novel opportunity to suppress oncogenic RAS signalling by altering its localization to endomembranes.”