# Targeting of PTP4A3 overexpression sensitises HGSOC cells towards chemotherapeutic drugs

## TL;DR

This study shows that targeting PTP4A3 in high-grade serous ovarian cancer can make cancer cells more responsive to chemotherapy drugs.

## Contribution

The study reveals that PTP4A3 inhibition can overcome compensatory mechanisms and sensitize HGSOC cells to chemotherapy.

## Key findings

- PTP4A3 overexpression promotes autophagy and chemoresistance in HGSOC cells.
- Inhibiting PTP4A3 with JMS-053 or shRNA sensitizes HGSOC cells to chemotherapeutic drugs.
- PTP4A3 inhibition is most effective in HGSOC cells with normal KRAS expression.

## Abstract

Ovarian cancer (OC) has the highest mortality rate of all gynaecological malignancies, partly attributable to its propensity for chemotherapy resistance. The most common subtype of OC is serous, of which high‐grade serous ovarian cancer (HGSOC) is the most lethal subtype. Protein tyrosine phosphatase 4A3 (PTP4A3) overexpression is implicated in tumour cell invasion and metastasis by upregulating the PI3K/Akt/mTORC1 axis. Previously, we reported that PTP4A3 increased the survival of non‐serous OC cells by activating the autophagy pathway. Here, we investigated the impact of PTP4A3 on cell proliferation, autophagy and chemoresistance in HGSOC cells and whether targeting PTP4A3 in HGSOC cells that overexpress this phosphatase would sensitise them to existing chemotherapeutic drugs. Gene silencing of PTP4A3 resulted in the upregulation of compensatory mechanisms that overcame the loss of PTP4A3 expression, but this was mitigated by pan‐PTP4A inhibition with JMS‐053 in HGSOC cells. Moreover, shRNA‐mediated silencing of PTP4A3 sensitised HGSOC cells to clinically relevant chemotherapeutic drugs. Overall, we show that compensatory mechanisms from PTP4A1 and PTP4A2 can arise when specifically targeting PTP4A3 in HGSOC and that pan‐PTP4A inhibition can overcome those effects.

In HGSOC with normal KRAS expression, high PTP4A3 expression regulates autophagy activation. Conversely, in HGSOC with high KRAS expression, KRAS dictates autophagy control, and PTP4A3 is not required. When high PTP4A3 expression is inhibited, HGSOC cells are preferentially sensitised towards DNA‐damaging agents. Thus, targeting PTP4A3 when highly expressed in OC may increase sensitivity to existing chemotherapy drugs.