Discovery of Major Subsets of KRAS Mutations in Lung Cancer Could Lead To New, Targeted Therapeutics

Discovery of Major Subsets of KRAS Mutations in Lung Cancer Could Lead To New, Targeted Therapeutics

Scientists at The University of Texas MD Anderson Cancer Center recently identified lung cancer subsets that harbor mutations in the KRAS gene, a gene involved primarily in regulating cell division, and with an established role in cancer progression. The team presented their latest findings during the section devoted to Oncogenic Signaling and Cell Death, in a presentation entitled “Co-occurring genomic alterations define major subsets of KRAS-mutant lung adenocarcinoma (LUAC) with distinct biology and therapeutic vulnerabilities,” at the American Association for Cancer Research (AACR) Annual Meeting on April 19, 2015 in Philadelphia.

The KRAS gene codes for the KRAS protein, which switches between an inactive and active state, acting as an on/off molecular switch — it is activated when bound to a GTP molecule, and inactivated when bound to another molecule, the GDP. Activating KRAS mutations have been detected in several types of human tumors, impairing the ability of KRAS protein to switch to its inactive states. This leads to uncontrolled cell proliferation and increased resistance to current therapeutics, such as chemotherapy. In lung cancers, researchers are presented with highly heterogeneous tumors for KRAS mutations, which hampers the development of effective targeted therapeutics.

In this new research, researchers developed a strategy to detect distinct subsets of KRAS-mutant LUAC. They analyzed 68 KRAS-mutant tumors, 88 additional chemo-naive KRAS-mutant LUACs (from PROSPECT study) and 36 platinum-refractory LUACs (from the BATTLE-2 clinical trial). The team identified three consensus and robust major subsets of KRAS-mutant LUAC among all the different groups of samples analyzed. These were characterized by co-occurring genomic alterations, specifically in the STK11/LKB1 and TP53 gene, accompanied by low expression of the TTF1 gene and CDKN2A/B gene inactivation, but with distinct patterns of intracellular signaling and therapeutic vulnerabilities.

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John Heymach, M.D., Ph.D., chair of Thoracic/Head & Neck Medical Oncology and study lead author noted, “The development of more effective treatments for LUAC-bearing activating mutations in KRAS has been hampered by the biological heterogeneity of KRAS-mutant tumors. The molecular underpinnings that drive this process are poorly characterized.”

Ferdinandos Skoulidis, M.D., Ph.D., instructor of Thoracic/Head & Neck Medical Oncology and study first author added, “Our work revealed three major subsets of KRAS-mutant LUAC, which were dominated by co-occurring genetic events, each biologically distinct and susceptible to different therapeutic strategies.”

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