Non-genetic adaptive resistance to KRASG12C inhibition: EMT is not the only culprit

Abstract

Adaptions to therapeutic pressures exerted on cancer cells enable malignant progression of the tumor, culminating in escape from programmed cell death and development of resistant diseases. A common form of cancer adaptation is non-genetic alterations that exploit mechanisms already present in cancer cells and do not require genetic modifications that can also lead to resistance mechanisms. Epithelial-to-mesenchymal transition (EMT) is one of the most prevalent mechanisms of adaptive drug resistance and resulting cancer treatment failure, driven by epigenetic reprogramming and EMT-specific transcription factors. A recent breakthrough in cancer treatment is the development of KRAS^G12C inhibitors, which herald a new era of therapy by knocking out a unique substitution of an oncogenic driver. However, these highly selective agents targeting KRAS^G12C, such as FDA-approved sotorasib (AMG510) and adagrasib (MRTX849), inevitably encounter multiple mechanisms of drug resistance. In addition to EMT, cancer cells can hijack or rewire the sophisticated signaling networks that physiologically control cell proliferation, growth, and differentiation to promote malignant cancer cell phenotypes, suggesting that inhibition of multiple interconnected signaling pathways may be required to block tumor progression on KRAS^G12C inhibitor therapy. Furthermore, the tumor microenvironment (TME) of cancer cells, such as tumor-infiltrating lymphocytes (TILs), contribute significantly to immune escape and tumor progression, suggesting a therapeutic approach that targets not only cancer cells but also the TME. Deciphering and targeting cancer adaptions promises mechanistic insights into tumor pathobiology and improved clinical management of KRAS^G12C-mutant cancer. This review presents recent advances in non-genetic adaptations leading to resistance to KRAS^G12C inhibitors, with a focus on oncogenic pathway rewiring, TME, and EMT.

Keywords: EMT; KRAS G12C inhibitors; TME; non-genetic adaptive resistance; symbiosis.

Figure 1

Oncogenic KRAS signaling pathway. KRAS switches between the GDP-bound inactive form and the GTP-bound active state, which is facilitated by GEFs and GAP, respectively. Activated RTKs relay extracellular signals from GRB2 to SOS, one of the major GEFs, to SHP2 and to KRAS. KRAS^G12C inhibitors (AMG510, MRTX849, etc.) preferentially target the GDP-bound inactive form of the KRAS protein and prevent its conversion to the active form (GTP-bound). The major signaling cascades upstream and downstream of KRAS are also highlighted. GAP, GTPase-activating protein; GEFs, guanine nucleotide exchange factors; GRB2, growth factor receptor-bound protein 2; P, phosphorylation; SHP2, Src homology region 2 domain-containing phosphatase-2; SOS, son of sevenless protein.

Figure 2

Symbiosis between cancer cells and the tumor microenvironment (TME). The infiltration and ratio of different lymphocytes are determined by the antigen presentation of cancer cells, which in return influences tumor growth and response to therapy. Hypoxia-inducible factors (HIF) and metabolites (e.g., lactate) also play a key role in reprogramming the TME of cancer. CD3⁺ T-lymphocyte: T cells that mediate the activation of tumor-reactive T cells, e.g., CD8⁺ naive T cells and CD4⁺ naive T cells. CD4⁺ T lymphocyte: also called T helper cell, which remodels TME by releasing cytokines and mediates the anti-tumor response of CD8⁺ T cells by cross-presentation of dendritic cells. CD8⁺ T lymphocytes: also called cytotoxic T cell, the specific killer that targets the surveilled cancer cells. Treg cells: also called suppressor T cells, a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosuppressive and generally suppress or downregulate the induction and proliferation of effector T cells. Treg cells express CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4⁺ cells. Since effector T cells also express CD4 and CD25, it is difficult to effectively distinguish Treg cells from effector CD4⁺ cells, making them difficult to study.

Figure 3

The interaction between KRAS signaling and EMT. The KRAS-MAPK pathway is important for the stability of CD274 (PD-L1) mRNAs. KRAS signaling and YAP/TAZ converge to activate transcriptional programs that regulates EMT and EMT is a key driver of tumor immune evasion. IGFR, insulin-like growth factor receptor; FGFR1, fibroblast growth factor receptor 1; TGF-β, transforming growth factor-beta; IFN-γ, interferon gamma; TNF-α, tumor necrosis factor-alpha; HIF-α, hypoxia-inducible factor-alpha; IL-6, interleukins 6; SNAI1, snail family transcriptional repressor 1.