The DNA damage response pathway as a land of therapeutic opportunities for colorectal cancer

Mauri, Gianluca; Arena, Sabrina; Siena, Salvatore; Bardelli, Alberto; Sartore-Bianchi, Andrea

doi:10.1016/j.annonc.2020.05.027

Cited by 63 publications

(64 citation statements)

References 137 publications

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“…110 As previously discussed, the therapeutic application of PARPi in CRC was recently addressed. 111 In a preclinical study of RAS or BRAF MT MSS CRC cells, around 13% of CRC lines (13/99) were highly sensitive to olaparib and displayed crosssensitivity to oxaliplatin, potentially underpinning a defect in the HR repair pathway. 112 Another potential tumor target is the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).…”

Section: Other Miscellaneous Approachesmentioning

confidence: 99%

Strategies to tackle RAS-mutated metastatic colorectal cancer

et al. 2021

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The RAS oncogene is among the most commonly mutated in cancer. RAS mutations are identified in about half of patients diagnosed with metastatic colorectal cancer (mCRC), conferring poor prognosis and lack of response to anti-epidermal growth factor receptor (EGFR) antibodies. In the last decades, several investigational attempts failed in directly targeting RAS mutations, thus RAS was historically regarded as 'undruggable'. Recently, novel specific KRAS G12C inhibitors showed promising results in different solid tumors, including mCRC, renewing interest in this biomarker as a target. In this review, we discuss different strategies of RAS targeting in mCRC, according to literature data in both clinical and preclinical settings. We recognized five main strategies focusing on those more promising: direct RAS targeting, targeting the mitogen-activated protein kinase (MAPK) pathway, harnessing RAS through immunotherapy combinations, RAS targeting through metabolic pathways, and finally other miscellaneous approaches. Direct KRAS G12C inhibition is emerging as the most promising strategy in mCRC as well as in other solid malignancies. However, despite good disease control rates, tumor response and duration of response are still limited in mCRC. At this regard, combinational approaches with anti-epidermal growth factor receptor drugs or checkpoint inhibitors have been proposed to enhance treatment efficacy, based on encouraging results achieved in preclinical studies. Besides, concomitant therapies increasing metabolic stress are currently under evaluation and expected to also provide remarkable results in RAS codon mutations apart from KRAS G12C . In conclusion, based on hereby reported efforts of translational research, RAS mutations should no longer be regarded as 'undruggable' and future avenues are now opening for translation in the clinic in mCRC.

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Section: Other Miscellaneous Approachesmentioning

confidence: 99%

Strategies to tackle RAS-mutated metastatic colorectal cancer

et al. 2021

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“…Nevertheless, studies with larger sample sizes and better coverage of DDR-related genes are pivotal for further verifications. Clinical explorations are also ongoing to use the poly (ADP-ribose) polymerase (PARP) inhibitors in colorectal cancer patients carrying DDR inactivation and have benefited from previous platinum chemotherapy ( 62 , 63 ). These findings may be useful for clinical decisions in patients with tumor characteristics associated with poor prognosis and risk stratification of patients in future clinical studies.…”

Section: Discussionmentioning

confidence: 99%

Mutated DNA Damage Repair Pathways Are Prognostic and Chemosensitivity Markers for Resected Colorectal Cancer Liver Metastases

et al. 2021

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Deficiency of the DNA damage repair (DDR) signaling pathways is potentially responsible for genetic instability and oncogenesis in tumors, including colorectal cancer. However, the correlations of mutated DDR signaling pathways to the prognosis of colorectal cancer liver metastasis (CRLM) after resection and other clinical applications have not been fully investigated. Here, to test the potential correlation of mutated DDR pathways with survival and pre-operative chemotherapy responses, tumor tissues from 146 patients with CRLM were collected for next-generation sequencing with a 620-gene panel, including 68 genes in 7 DDR pathways, and clinical data were collected accordingly. The analyses revealed that 137 of 146 (93.8%) patients had at least one mutation in the DDR pathways. Mutations in BER, FA, HRR and MMR pathways were significantly correlated with worse overall survival than the wild-types (P < 0.05), and co-mutated DDR pathways showed even more significant correlations (P < 0.01). The number of mutated DDR pathways was also proved an independent stratifying factor of overall survival by Cox multivariable analysis with other clinical factors and biomarkers (hazard ratio = 9.14; 95% confidence interval, 1.21–68.9; P = 0.032). Additionally, mutated FA and MMR pathways were positively and negatively correlated with the response of oxaliplatin-based pre-operative chemotherapy (P = 0.0095 and 0.048, respectively). Mutated DDR signaling pathways can predict pre-operative chemotherapy response and post-operative survival in CRLM patients.

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“…PARP inhibitors are active against cancer cells harboring DDR (DNA damage response) alterations, whose efficacy was initially recognized in breast and ovarian cancers, and currently extended to prostate and pancreatic cancer [107]. In CRC, the role of DDR alterations is still widely unknown and only few data about their clinical impact are available [108].…”

Section: Temozolomide + Immune Checkpoint Inhibitorsmentioning

confidence: 99%

Immune Checkpoint Inhibitors in pMMR Metastatic Colorectal Cancer: A Tough Challenge

Marmorino

Boccaccino

Germani

et al. 2020

Cancers

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The introduction of checkpoint inhibitors provided remarkable achievements in several solid tumors but only 5% of metastatic colorectal cancer (mCRC) patients, i.e., those with bearing microsatellite instable (MSI-high)/deficient DNA mismatch repair (dMMR) tumors, benefit from this approach. The favorable effect of immunotherapy in these patients has been postulated to be due to an increase in neoantigens due to their higher somatic mutational load, also associated with an abundant infiltration of immune cells in tumor microenvironment (TME). While in patients with dMMR tumors checkpoint inhibitors allow achieving durable response with dramatic survival improvement, current results in patients with microsatellite stable (MSS or MSI-low)/proficient DNA mismatch repair (pMMR) tumors are disappointing. These tumors show low mutational load and absence of “immune-competent” TME, and are intrinsically resistant to immune checkpoint inhibitors. Modifying the interplay among cancer cells, TME and host immune system is the aim of multiple lines of research in order to enhance the immunogenicity of pMMR mCRC, and exploit immunotherapy also in this field. Here, we focus on the rationale behind ongoing clinical trials aiming at extending the efficacy of immunotherapy beyond the MSI-high/dMMR subgroup with particular regard to academic no-profit studies.

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The DNA damage response pathway as a land of therapeutic opportunities for colorectal cancer

Cited by 63 publications

References 137 publications

Strategies to tackle RAS-mutated metastatic colorectal cancer

Strategies to tackle RAS-mutated metastatic colorectal cancer

Mutated DNA Damage Repair Pathways Are Prognostic and Chemosensitivity Markers for Resected Colorectal Cancer Liver Metastases

Immune Checkpoint Inhibitors in pMMR Metastatic Colorectal Cancer: A Tough Challenge

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