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Review
. 2022 Jan 4;5(1):36-63.
doi: 10.20517/cdr.2021.96. eCollection 2022.

Emerging actionable targets to treat therapy-resistant colorectal cancers

Emanuela Grassilli  1 , Maria Grazia Cerrito  1
Affiliations
Review

Emerging actionable targets to treat therapy-resistant colorectal cancers

Emanuela Grassilli et al. Cancer Drug Resist. .

Abstract

In the last two decades major improvements have been reached in the early diagnosis of colorectal cancer (CRC) and, besides chemotherapy, an ampler choice of therapeutic approaches is now available, including targeted and immunotherapy. Despite that, CRC remains a "big killer" mainly due to the development of resistance to therapies, especially when the disease is diagnosed after it is already metastatic. At the same time, our knowledge of the mechanisms underlying resistance has been rapidly expanding which allows the development of novel therapeutic options in order to overcome it. As far as resistance to chemotherapy is concerned, several contributors have been identified such as: intake/efflux systems upregulation; alterations in the DNA damage response, due to defect in the DNA checkpoint and repair systems; dysregulation of the expression of apoptotic/anti-apoptotic members of the BCL2 family; overexpression of oncogenic kinases; the presence of cancer stem cells; and the composition of the tumoral microenvironment and that of the gut microbiota. Interestingly, several mechanisms are also involved in the resistance to targeted and/or immunotherapy. For example, overexpression and/or hyperactivation and/or amplification of oncogenic kinases can sustain resistance to targeted therapy whereas the composition of the gut microbiota, as well as that of the tumoral niche, and defects in DNA repair systems are crucial for determining the response to immunotherapy. In this review we will make an overview of the main resistance mechanisms identified so far and of the new therapeutic approaches to overcome it.

Keywords: BRAF; Colorectal cancer; EGFR; ERBB2; MET; chemotherapy; gut microbiota; immune checkpoint inhibitors; kinase inhibitors; resistance; target therapy.

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Conflict of interest statement

Both authors declared that there are no conflicts of interest.

Figures

Figure 1
Figure 1
Mechanisms of resistance to chemotherapy. Tumor cell-intrinsic mechanisms may involve: dysregulated expression of drug transporters (SLC family members or ATP7B) and enzymes involved in drug metabolism (CYP family members), imbalanced expression of anti-/pro-apoptotic molecules (BAX mutation/loss or increased BCL2 expression), or dysregulation of DNA repair mechanisms and checkpoints (TP53 mutation/loss, MMR proteins mutation, diminished expression of BER proteins, or increased ERCC6 expression). External signals acting on the tumor cells to trigger resistance may derive from the cells populating the tumoral niche such as the CAFs releasing TGFB, osteopontin and exosomes containing specific lncRNAs and miRs. In addition, inflammatory and immunitary cells of the niche release a number of interleukins, growth factors, pro-angiogenic factors. Also, specific components of the microbiota can contribute to the resistance to chemotherapy by directly inactivating the drug (Gammaproteobacterial or M. hyorhinis) or by engaging the TLR4/MyD88 system to transduce pro-survival and autophagic signals. SLC: Solute carrier; MMR: mismatch-repair system; CAFs: cancer-associated fibroblast.
Figure 2
Figure 2
Mechanisms of resistance to targeted therapy against EGFR and mutated BRAF. Intrinsic resistance to EGFR blockade by panitumumab (Pani) and cetuximab (Cetu) occurs in case of activating mutations in the EGFR and its downstream effectors such as RAS, BRAF, and PIK3CA and when there is loss of PTEN either due to truncation or deletion. Acquired resistance stems from stimulation of collateral pathways impinging on the same downstream signaling activated by EGFR (i.e., the RAS/MAPK and the PIK3/AKT pathways). Hyperactivation of these pathways may be due to overexpression or mutation of ERBB2, heterodimerization of ERBB2 and ERBB3, engagement of the EGFR by TGFA which in turn activates MET, MET overexpression, EPHA2 overexpression, or IGF1R engagement. Strategies to overcome the insensitivity to EGFR blockade are directed at the inhibition of the collateral signaling such as using ERBB2 blocking agents trastuzumab (Trast) and lapatinib (Lapa) and the MET inhibitors crizotinib (Crizo) and capmatinib (Cap). Resistance to the mutated BRAF inhibitor vemurafenib (Vemu) originates from the shifting in the choice of the dimerization companion. In the resistant cells instead of mutated BRAF homodimers, mutated BRAF/CRAF heterodimers are formed which are insensitive to the inhibitor and thus MAPK activation is refueled. To prevent hetodimerization a novel inhibitor, that specifically bind mutated BRAF homodimers has been developed. Another route of escape to mutant BRAF blockade has been described where activation of the WNT/β-catenin signaling is triggered via FAK. Both MAPK and β-catenin signaling eventually activate a series of transcription factors (TFs) responsible for the transcription of proliferative genes. Currently, to prevent resistance to BRAF inhibition, a vertical blockade of the pathway is being tested in clinical trials using vemurafenib in combination with a MEK inhibitor such as cobimetinib (Cobi) or trametinib (Trame). Mutated proteins are indicated by the red stars and the italicized name.
Figure 3
Figure 3
Mechanisms of resistance to anti-angiogenic therapy. Hyperproduction of VEGFA is a consequence of the hypoxic status in the center of the tumor which activates HIF1A, a transcription factor that regulates VEGFA transcription. Overproduction of VEGFA can be blocked by monoclonal antibodies (bevacizumab, Beva) or a VEGF-trap (aflibercept, Afli). Alternatively, the signal can be blocked downstream of the dedicated receptor by small kinase inhibitors like regorafenib (Rego), which can also inhibit the TIE2 receptor, thus imposing a double anti-angiogenic blockade. In fact, both receptors are critical in stimulating the proliferation and migration of the endothelial cells, necessary for the formation of new vessels into and around the tumor mass. In particular, TIE2 receptor is regulated by ANGPT1 and 2, the former inducing signals involved in maturation and stabilization of blood vessels, whereas the latter blocks this signaling and triggers remodeling of vascular sprouts. Overproduction of ANGPT2 can drive a parallel neo-angiogenic signaling when VEGR-driven signaling is impeded by Beva-based therapy. In addition, another parallel neo-angiogenic pathway that can act as an escape route to VEGFA blockade is initiated by TGFB binding to a multimeric receptor formed by a TGFB2 dimer in complex with an activin receptor-like kinase 1 (ACVRL1) dimer.
Figure 4
Figure 4
Mechanisms of resistance to immuno-therapy. Cancer cells can express several immunosuppressive molecules that can be blocked using specific inhibitors in order to re-activate the anti-tumor immune response. Often, they are redundant so that the re-activation of one pathway may be compensated by hyperactivation of a different immunosuppressive route so that resistance to therapy is the result. Resistance to anti-PD1 blockade may be due to overproduction and release of VEGFA, as well as by overexpression of IDO1 with consequent increased levels of kynurein in the microenvironment. Specific components of the microbiota are also necessary for the successful blockade of PD-1 and CTL-A4 indicating that antibiotics may represent a resistance factor to ICIs. Finally, concurrent blockade of two or more immune checkpoints has been shown to improve the response and overcome the resistance to ICIs. Pembro: Pembrolizumab; Nivo: nivolumab; Rela: relatlimab; Ipi: ipilumab; IDO1: indoleamine 2, 3-dioxygenase 1.
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