Overcoming Resistance to Drugs Targeting KRASG12C Mutation

Abstract

Activating KRAS mutations are present in 25% of human cancer. Although oncogenic Ras was deemed "undruggable" in the past, recent efforts led to the development of pharmacological inhibitors targeting the KRAS^G12C mutant, which have shown promise in early clinical trials. The development of allele-specific K-Ras^G12C inhibitors marked a new chapter in targeting oncogenic KRAS mutant in cancer. However, drug resistance against these new drugs will likely limit their efficacy in the clinic. Genome-wide approaches have been used to interrogate the mechanisms of resistance to K-Ras^G12C inhibitors, which would facilitate the development of therapeutics overcoming drug resistance. This article reviews the latest progress in resistance to K-Ras^G12C-targeted therapies and aims to provide insight in future research targeting drug resistance in cancer.

Keywords: DRUG RESISTANCE; KRAS INHIBITOR; ONCOGENE; TARGETED THERAPY.

Graphical abstract

Figure 1

Ras Signaling Pathway. In normal physiological conditions, the binding of receptor tyrosine kinases (RTKs) with growth factors activate SHC-GRB2-SOS1 complex, which induces the formation of active GTP-bound Ras proteins. Downstream signals of Ras GTP include the activation of MAPK/ERK and PI3K/AKT/mTORC1 signaling pathways, which promotes cell growth. GEF, guanine nucleotide exchange factor; GAP, GTPase-activating protein.

Figure 2

Chemical Structures of K-Ras^G12C Inhibitors.

Figure 3

Intrinsic Resistance to Drugs Targeting K-Ras^G12C. (A) K-Ras^G12C inhibitors function mainly through suppressing the MAPK/ERK signaling pathway and variably affecting other growth-promoting signaling pathways, including the PI3K/AKT/mTORC1 pathway. (B and C) However, the extent to which cell proliferation depends on the MAPK/ERK pathway varies across models. KRAS^G12C mutant cells that heavily depend upon MAPK/ERK signaling for proliferation are highly sensitive to K-Ras^G12C inhibitors (B). Otherwise, cells will be refractory to K-Ras^G12C inhibition (C). (D) Secondary KRAS mutations conferring either increased GEF activity or decreased GAP activity to K-Ras protein will result in resistance to K-Ras^G12C inhibitors. (E) The mutation status of KRAS^G12C may be heterogeneous among primary tumor and metastases, as well as across individual intratumor cancer cells, which leads to inconsistent responses to K-Ras^G12C inhibitors among patients.

Figure 4

Acquired Resistance to Drugs Targeting K-Ras^G12C. (A) Steady state of KRAS mutant cells. Activating mutations of KRAS genes confer resistance to GAP-mediated K-Ras GTP hydrolysis, leading to uncontrolled activation of K-Ras downstream signaling and tumor growth. (B) Initial response to K-Ras^G12C inhibition. K-Ras^G12C inhibitors function by locking K-Ras^G12C in its GDP-binding state and hence suppress MAPK/ERK signaling and tumor growth. (C) Adaptive resistance to K-Ras^G12C inhibition. After initial response, ERK-mediated feedback inhibition of vertical RTKs/SHP2 pathway is lifted, which induces the activation of N-Ras, H-Ras, and K-Ras^G12C. Given that RTKs/SHP2 signaling pathway is hyperactive in this stage, newly synthesized K-Ras^G12C immediately binds with GTP, potentiating the feedback adaptive resistance. In addition, AURKA operates by interacting with GTP-bound K-Ras^G12C and promotes downstream RAF activation. Consequently, ERK is reactivated and tumor growth is resumed.