Emerging actionable targets to treat therapy-resistant colorectal cancers

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.

HIF1A overexpression predicts the high lymph node metastasis risk and indicates a poor prognosis in papillary thyroid cancer

“…Hypoxia is a common condition found in a range of solid tumors, which plays an essential role in tumor occurrence and development [ 27 ]. Tumor cells adapt to a hypoxic environment mainly regulated by HIF-1 [ 28 ]. As a subunit of HIF-A, HIF1A has been implicated as a tumor promoter gene, which was overexpressed in tumors of the ovarian, bladder, and prostate [ [29] , [30] , [31] ].…”

Potential role of the Eph/ephrin system in colorectal cancer: emerging druggable molecular targets

“…Most importantly, the high expression of EphA2 in many CRCs may make it a potential target for therapy in this disease ( 74 , 81 ). In this regard, high EphA2 receptor expression in CRC modulates a mechanism of primary and acquired resistance to cetuximab ( 82 , 83 ).…”

Insights into fourth generation selective inhibitors of (C797S) EGFR mutation combating non-small cell lung cancer resistance: a critical review

“…A ligand extension strategy was applied to the lead compound EAI045 ( 13) by adding a phenyl-piperazine moiety to the para substitution of isoindolinone ring. With an IC 50 value of 0.1 mM, the newly developed drug (39) was relatively the most potent against the mutant EGFR L858R/T790M/C797S . 108 The phenylpiperazine extension could provide better exposure to the allosteric pocket to have better binding (Fig.…”

“…As well as, N-(4-Fig. 25 The optimization process of compound (39). 45) with highly selective but modest action that inhibits EGFR del19/T790M/C797S at IC 50 = 790 nM through a library of selective kinase inhibitors.…”