Tailoring Tyrosine Kinase Inhibitors to Fit the Lung Cancer Genome - Article Example

Even earlier to the advent of genome sequencing, traditional biological approaches had shown genetic alterations were a characteristic of NSCLC, making personalised treatment favored in the case of NSCLC. A key understanding was that genetic alterations to critical growth factor signalling pathways regulated cell proliferation, survival, and migration. The kinase cascades were responsible to a large extent on signal propagation along these pathways, making inhibition of kinase enzymatic function an important target for chemotherapies in the treatment of NSCLC.

The tyrosine kinase family of signalling enzymes became the focus of this strategy leading to the development of a range of TKIs, with the promise of potential for more novel TKIs. (2) The TKIs approach to the treatment of NSCLC, while evincing success, also demonstrates the problems that arise in the use of targeted therapeutics for the treatment of genetically heterogeneous populations. Targeted therapies in cancer treatment like TKIs in NSLC are based on the assumption that the specific target has been definitely identified and that focusing on this single target or a narrow range of well defined targets is adequate in the treatment of the tumor.

However, the recent advances in genome sequencing studies have indicated that this basis for NSCLC may not be true, since the possibility of a single genetic event in heterogeneous population is only 15% to 20%, with a majority of the patients showing unique combinations of mutations in many of the known oncogenes and tumor suppressors. This definitely points to heterogeneity and mutational redundancy as the primary reasons for resistance to TKIs therapy in NSCLC and the poor response to this treatment approach. (3). With definite identification of the key driver mutations critical to the success of targeted therapies reliable genetic information becomes very important, and in its absence only therapy decisions are restricted to the histology of the disease.

The availability of genetic information changes this dimension, as more reliable and precise treatment decisions can be taken. Assuming that it is possible to correctly segregate NSCLC patients based on genetic information, then the next question that arises is what is the treatment approach fro each class of tumors. Activation of KRAS mutations are the most commonly seen genetic drivers in lung cancer, and targeting of the downstream signalling effecters or the metabolic by products of Ras transformation is the most promising approach in the treatment of Ras-driven tumors.

Activating mutations to a variety of tyrosine kinases are the drivers for the other two classes of NSCLC. These two classes represent between 40% to 80% of all NSCLCs. This shows the possible usefulness of targeted TKI therapy in case the correct target for tumor is identified. Advances in genome sequencing make this correct target identification more of a reality. (4). The quinazoline class of small small-molecule TKIs targeted to EGFR constitute the most studied treatment for NSCLC. Pre-clinical models suggested that this mode of treatment would be effective, but in actual practice the response was