“The research, published in the journal Oncotarget, explored tumour heterogeneity – where different cells have different appearances or their own DNA signatures within the same cancer. Such differences could make it difficult to design effective, targeted treatment strategies.
“Firstly they confirmed the mutual exclusivity between the EGFR mutation and either the KRAS or BRAF mutation. Secondly, they found that lung cancers driven by the EGFR gene mutation have that specific mutation present uniformly throughout the tumour, regardless of microscopic appearance. In stark contrast, they discovered that some tumours, with either KRAS or BRAF gene mutations, do not have the mutation present in all parts of the tumour. ”
Editor’s note: In recent years, lung cancer treatment has focused on the use of targeted therapy drugs. These drugs kill tumor cells that have certain cancer-causing genetic mutations, while generally leaving healthy cells unharmed. Oncologists use genetic testing to see if a patient’s tumor has any specific genetic mutations that can be targeted by a specific drug. According to the research described here, different parts of a tumor may have different mutations that can be targeted by different drugs. This makes treatment more complicated, but continued research could lead to more effective treatments.
Abnormalities in the KRAS gene are the most common mutations in lung cancer, especially in lung adenocarcinoma, a type of non-small cell lung cancer (NSCLC). However, no effective targeted therapy directed at KRAS has been found. Instead, researchers have begun to focus on blocking molecules “downstream” in the chain of chemical reactions through which KRAS affects the cell. Two such molecules are TBK1 and MEK. A recent study found that the drug CYT387 blocks TBK1. CYT387 reduced tumor growth in mice with KRAS-mutant lung adenocarcinoma. Also in mice, CYT387 and the MEK inhibitor AZD6244, given together, shrank aggressive lung tumors with mutations in both the KRAS and the TP53 gene. Researchers now hope to investigate the two drugs in people.
E-cigarettes (electronic cigarettes that use a battery-powered system to deliver nicotine without producing smoke) are advertised as a safer alternative to tobacco cigarettes. However, very few studies have investigated how e-cigarettes affect lung function and lung cancer risk. Researchers examined human airway cells with mutations in the TP53 and KRAS genes, which are often mutated in the airways of current or former smokers at high risk of lung cancer. When the cells were exposed to e-cigarette vapor, they developed cancer-cell-like behaviors and gene expression changes very similar to what was seen when these cells were exposed to tobacco smoke. E-cigarettes may increase the risk of developing lung cancer in high-risk people, including current and former tobacco smokers.
Mutations in the KRAS gene are the most common cancer-driving mutations in all cancers; they occur in 20% of lung cancers and 40% of colon cancers. KRAS-mutant cancers are aggressive and do not respond well to current treatments. Although the importance of KRAS mutations in cancer has been known for over 30 years, scientists have so far not succeeded in developing a drug targeting them. Now researchers have located a previously undetected ‘pocket’ on a certain mutated form of the KRAS protein. The mutation, called KRAS(G12C), occurs in 7% of lung cancer and 9% of colorectal cancer patients. The researchers then created molecules that bind to the ‘pocket’ and inhibit the mutant KRAS, but not normal KRAS protein. They hope to develop these compounds into drugs against KRAS-mutant cancers.
Lee YS, Lee JW, Jang JW, Chi XZ, et al. Cancer Cell. Nov 11, 2013.
“A functional genetic screen of a fly mutant library and molecular analysis in cultured cell lines revealed that Runx3 forms a complex with BRD2 in a K-Ras-dependent manner in the early phase of the cell cycle; this complex induces expression of p14ARF/p19Arf and p21WAF/CIP. When K-Ras was constitutively activated, the Runx3-BRD2 complex was stably maintained and expression of both p14ARF and p21WAF/CIP was prolonged. These results provide a missing link between oncogenic K-Ras and the p14ARF-p53 pathway, and may explain how cells defend against oncogenic K-Ras.”
Castellano E, Sheridan C, Thin MZ, Nye E, et al. Cancer Cell. Nov 11, 2013.
“RAS proteins directly activate PI3-kinases. Mice bearing a germline mutation in the RAS binding domain of the p110α subunit of PI3-kinse are resistant to the development of RAS-driven tumors. However, it is unknown whether interaction of RAS with PI3-kinase is required in established tumors. The need for RAS interaction with p110α in the maintenance of mutant Kras-driven lung tumors was explored using an inducible mouse model.”
New research provides compelling evidence that targeted treatments benefit people with lung cancer. Researchers at 14 U.S. centers found that of nearly 1,000 people with lung cancers who were tested for 10 genetic abnormalities, 63% had an abnormality and 23% of these were treated with the appropriate targeted therapy. Those who received targeted treatments lived 1.5 times longer than those who did not (a median of 3.5 vs 2.4 years, respectively). People with ALK abnormalities lived longest at 4.3 years; followed by those with sensitizing EGFR mutations at 4.0 years; other EGFR mutations at 3.3 years; and KRAS mutations at 2.4 years. These findings were presented at the 2013 World Conference on Lung Cancer.
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.
Shimamura T, Chen Z, Soucheray M,Carretor J, et al. Clinical Cancer Research. Sept 17, 2013.
The recent discovery, in hematologic malignancies, that BET bromodomain inhibition impairs MYC expression and MYC transcriptional function established the rationale of targeting KRAS-driven NSCLC with BET inhibition. We performed functional assays to evaluate the effects of JQ1 in genetically defined NSCLC cells lines harboring KRAS and/or LKB1 mutations.
Bromodomain inhibition comprises a promising therapeutic strategy for KRAS mutant NSCLC with wild-type LKB1, via inhibition of MYC function.