Different mechanisms of resistance may be applicable to different types of cancer, likely depending on the germline or other mutation profile, or other factors, such as origin of the disease or prior treatment. This is a complex and rapidly evolving area, and one that is still in its relative infancy, but this section will outline some insights into mechanisms of resistance from preclinical studies.
1. Restoration of HRR is one mechanism leading to PARP inhibitor resistance, and can occur via several routes:
BRCA reversion mutations can restore protein function and lead to PARP inhibitor and platinum-based chemotherapy resistance .
- There are documented cases of BRCA1 reversion mutations exhibiting a MMEJ signature, suggesting that POLQ (required for MMEJ) could be a driver of resistance .
- Restoration of BRCA1 via other mechanisms than restoration mutations (e.g. alternative splicing or alternative translation initiation) [3-5].
- Mutations that compromise regulation of DNA end-resection via loss of 53BP1, MAD2L2/Rev7 or the Shieldin complex and enable HRR in the absence of BRCA1 [6-10].
- The two main repair pathways for double-strand break (DSB) repair are HRR and NHEJ. While HRR allows for precise repair, NHEJ is more error-prone. DNA end resection of DSB is an important step in HRR repair, as it produces 3’ overhangs that prevent NHEJ and allow proteins involved in HRR repair to be recruited .
2. POLQ inhibitors may suppress acquired PARP inhibitor resistance, whilst also conferring Synthetic Lethality in HRR and NHEJ deficient cancers .
3. Loss of PARP1 activity caused by mutations in the PARP1 DNA binding domain can cause PARP inhibitor resistance and impair PARP1 trapping .
4. Stabilisation of stalled replication forks has recently emerged as another novel PARP inhibitor resistance mechanism. It has been shown that loss of PTIP (the MLL3/4 complex protein) protected BRCA2-deficient cells from DNA damage by inhibiting the recruitment of the MRE11 nuclease, and subsequent DNA degradation of stalled replication forks, which prevented PARP inhibitor-induced lethality .
5. PARP-inhibitor resistant, BRCA1-deficient cells, are known to become dependent on ATR for survival .
6. Activation of trans-lesion DNA synthesis through loss of CHD4 promotes resistance by allowing less efficient DNA repair to occur .
7. Upregulation of the PgP transporter for drug efflux, resulting in reduced availability of PARP inhibitor . The next generation PARP inhibitor AZD2461, which has poor PgP affinity, may prove to overcome this mechanism of resistance .
8. PARG mutations can lead to PARP resistance via a mechanism that doesn’t restore HRR. Loss of PARG results in PAR chains not being degraded, so PARP activity has a bigger manifestation than it otherwise would and is not blocked by normal doses of PARP inhibitors .
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