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.

Keywords: KRAS mutation; adagrasib; drug resistance; non-genetic mechanisms; sotorasib.

Figure 1

KRAS codon 12 mutational signature in lung and pancreatic cancer landscape. (A) KRAS G12C mutation is more prevalent in non-small cell lung cancer (~40%) compared to the KRAS G12D mutation. (B) Conversely, in pancreatic cancer, KRASG12D mutation is the most frequently observed mutation. Cancer cells with the respective mutations are favored for their fitness in the fitness landscapes prevailing in the lung and pancreas, respectively. Figure 1 was made using BioRender.com (1 September 2023).

Figure 2

Structure and sequence of KRAS4B. (A) Crystal structure of wild-type (WT) KRAS with GDP bound (PDB ID: 4obe). The C-terminal HVR is not present in the structure. (B) 2D depiction of the secondary structure of KRAS. Disordered regions are indicated by lines. (C) Sequence of KRAS4B. The most common mutation hotspots are indicated by arrows. Selected structural regions in all (A–C) are highlighted with the following color scheme: P-loop (residues 10–14), orange; switch-I (residues 30–40), red; switch-II (residues 58–72), blue; HVR (residues 167–188), green. Adapted from [56].

Figure 3

Schematic representation of intrinsic and acquired drug resistance. In the case of intrinsic resistance, tumor cells can become resistant due to mutations that exist a priori. In the case of acquired resistance they can acquire resistance through non-genetic mechanisms initially and then followed by genetic changes. Figure 3 was made using BioRender.com (1 September 2023).