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 KRASG12C inhibitors, which herald a new era of therapy by knocking out a unique substitution of an oncogenic driver. However, these highly selective agents targeting KRASG12C, 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 KRASG12C 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 KRASG12C-mutant cancer. This review presents recent advances in non-genetic adaptations leading to resistance to KRASG12C inhibitors, with a focus on oncogenic pathway rewiring, TME, and EMT.

FBXL16 promotes cell growth and drug resistance in lung adenocarcinomas with KRAS mutation by stabilizing IRS1 and upregulating IRS1/AKT signaling

“…While KRAS was historically described as “undruggable”, novel covalent inhibitors specifically targeting KRASG12C, such as sotorasib (AMG‐510), were recently approved for the treatment of NSCLC patients harboring KRASG12C mutation [7,24–26]. Unfortunately, intrinsic and acquired resistance to KRASG12C inhibitors has already been extensively documented [4,27–29]. Given the significant upregulation of FBXL16 in LUADs with KRAS mutations, we hypothesized that FBXL16 might contribute to resistance to KRASG12C inhibitors.…”

“…Unfortunately, patients either have intrinsic resistance to these drugs or inevitably develop resistance upon drug treatment [4,27,[29][30][31][32]. Thus, it is urgently needed to identify new therapeutic targets upon which drug(s) can be developed for preventing or overcoming KRAS mutant inhibitor resistance.…”

“…While KRAS activating mutations occur frequently in NSCLCs, there had been no targeted therapy available for treating this subtype of lung cancer until the recent approval of covalent inhibitors (e.g., sotorasib and adagrasib) specifically targeting KRASG12C for the treatment of patients with advanced NSCLC [5,7,8]. Unfortunately, patients either have intrinsic resistance to these drugs or inevitably develop resistance upon drug treatment [4,27,29–32]. Thus, it is urgently needed to identify new therapeutic targets upon which drug(s) can be developed for preventing or overcoming KRAS mutant inhibitor resistance.…”

“…Unfortunately, intrinsic and acquired resistance to KRASG12C inhibitors has already been extensively documented [4,[27][28][29]. Given the significant upregulation of FBXL16 in LUADs with KRAS mutations, we hypothesized that FBXL16 might contribute to resistance to KRASG12C inhibitors.…”

Pharmacologically targeting KRASG12Din PDAC models: tumor cell intrinsic and extrinsic impact

“…18.533261 doi: bioRxiv preprint (ie. Sotorasib) can have clinical activity in PDAC 24 , although there are clearly distinct mechanisms through which resistance can emerge 25,26 The most prevalent KRAS mutation in PDAC is G12D 10,27 . Recently the agent MRTX1133 was described as a highly-selective and potent inhibitor of G12D, which has been shown to have efficacy in PDAC models 28,29 .…”