A Nexus between Genetic and Non-Genetic Mechanisms Guides KRAS Inhibitor Resistance in Lung Cancer

Abstract

Several studies in the last few years have determined that, in contrast to the prevailing dogma that drug resistance is simply due to Darwinian evolution—the selection of mutant clones in response to drug treatment—non-genetic changes can also lead to drug resistance whereby tolerant, reversible phenotypes are eventually relinquished by resistant, irreversible phenotypes. Here, using KRAS as a paradigm, we illustrate how this nexus between genetic and non-genetic mechanisms enables cancer cells to evade the harmful effects of drug treatment. We discuss how the conformational dynamics of the KRAS molecule, that includes intrinsically disordered regions, is influenced by the binding of the targeted therapies contributing to conformational noise and how this noise impacts the interaction of KRAS with partner proteins to rewire the protein interaction network. Thus, in response to drug treatment, reversible drug-tolerant phenotypes emerge via non-genetic mechanisms that eventually enable the emergence of irreversible resistant clones via genetic mutations. Furthermore, we also discuss the recent data demonstrating how combination therapy can help alleviate KRAS drug resistance in lung cancer, and how new treatment strategies based on evolutionary principles may help minimize or even preclude the emergence of drug resistance.

Leveraging Cancer Phenotypic Plasticity for Novel Treatment Strategies

“…In response to chronic drug treatment, however, the PIN is frustrated and mutations in specific proteins that occupy key positions in the PIN are introduced to relieve frustration. This results in irreversible drug resistance [ 10 , 11 ]. In fact, in bacteria too, it has been observed that in the short-term, the microbes acclimate to stress through phenotypic plasticity, but in the longer term, they adapt to stress genetically [ 12 ].…”

“…Together, these observations lend further credence to the idea that phenotypic plasticity is of fundamental importance in developing drug resistance and speeding up the evolution of bacteria and cancer cells [ 14 ] ( Figure 1 ). Furthermore, group behavior emerging from phenotypic plasticity can sustain a heterogeneous cancer cell population with multiple interchangeable phenotypes, producing temporary drug tolerance and facilitating the initiation and progression to permanent drug resistance [ 4 , 7 , 10 , 11 , 15 ].…”