Resistance to targeted therapy remains a major challenge in oncology. Resistance comes in two flavors: (1) early intrinsic resistance (also known as innate or de novo resistance) or fast adaptive tumor responses, and (2) late acquired resistance, resulting from clonal evolution of resistant variants.
It is revealed recurrent somatic alterations in several genes are considered to be drivers of oncogenesis. They activate crucial oncoproteins such as RAS, BRAF, EGFR, PIK3CA, ALK, BCR-ABL and many others. These driver alterations can give rise to a tumor dependency on a particular signaling pathway or module. These dependencies, called ‘oncogene addiction’, can result from activation of genes that stimulate a pathway or inactivation of genes that inhibit a signaling pathway. Tumor dependencies can also be the result of other factors, like hormone dependency or lineage dependency. The addiction of certain cancer types to specific signaling pathways or modules in those pathways creates an Achilles heel for tumor maintenance that can be exploited therapeutically. However, examples of pure ‘oncogene addiction’ from a single oncogenic event are rare. Most cancers contain many mutations, making such tumors potentially less dependent on a single oncogenic event. Another complication is that signaling pathways are interconnected and these interactions are often dynamic. A third factor limiting the success of targeted single-agent therapy is the heterogeneity of tumors, especially in the advanced or metastatic setting.
An understanding of the recurrent patterns of resistance is necessary to design strategies to overcome intrinsic resistance and delay acquired resistance to targeted cancer drugs. To address this, significant efforts are now underway to (1) develop better drugs or more effective drug combinations to fully suppress the oncogenic signaling pathways and (2) development of non-invasive assays to monitor drug response and the emergence of drug resistance
Groenendijk F H et al. Drug resistance to targeted therapies: Deja vu all over again[J]. Molecular oncology, 2014, 8(6): 1067-1083.