HCQ explains its antitumor activity thanks to its ability to inhibit autophagy. HCQ is, indeed, an FDA-approved drug inhibiting autophagy [135]. Several types of tumors develop chemoresistance by enhancing autophagic flux. Autophagy consists in the sequestration of materials in autophagic vesicles to be eliminated through lysosomal fusion and allows cells to overcome metabolic and therapeutic stresses. By recycling intracellular components, cells may maintain an energy balance and increase their growth. If it occurs in cancer cells, resistance mechanisms may establish. One of the mechanisms responsible for drug resistance is related to increased drug efflux by ATP-binding cassette (ABC) transporters [136,137]. It has been observed that HCQ is significantly reduced the increase in P-gp (ABCB1) expression and, in combination with several anticancer drugs, induced higher cytotoxicity in refractory cancers by inhibiting autophagic activity [138]. However, the role of autophagy in cancer is controversial and depends on genotype and tumor stage development [139]. Many clinical trials examined the synergistic effects of the addition of HCQ to conventional chemotherapic drugs, finding that the role of autophagy is complex and is influenced by several factors. Depending on genetic concomitant alterations, autophagy may possess both pro-tumorigenic and tumor-suppressive roles. It has been confirmed in murine models of pancreatic ductal adenocarcinoma, a type of cancer with a high mortality rate, due to its refractoriness to therapies. Mice presenting activated oncogenic KRAS and normal expression of p53 oncosuppressor experienced a critical regression of tumor developing under HCQ (60 mg/kg/day i.p.). By contrast, in those with a deficiency of p53, the inhibition of autophagy by HCQ increased the tumor progression, demonstrating that autophagy’s role in tumorigenesis is strictly related to the expression of p53 [140]. The expression of p53 is often altered in cancer, so as to be found mutated or absent in the 75% of pancreatic ductal adenocarcinomas [141]. This issue highlights the necessity to carefully evaluate the use of HCQ in certain tumor types. Different outcomes have been previously described, it has been found that inhibition of autophagy by HCQ might arise as a valuable adjuvant in pancreatic ductal adenocarcinoma chemotherapy, regardless of p53 status [142,143]. Given the same doses and route of administration, these inconsistencies between the two reported studies could probably derive from the use of p53 homozygous and heterozygous models of mice, respectively. Regarding KRAS oncoprotein, its downstream pathway is one of the major players of pancreatic carcinogenesis. The inhibition of this pathway by cytotoxic drugs, as well as trametinib, is often associated with an increase in autophagy. For this reason, Drucker and Rosen [144] performed an off-label trial with an association of 400–1200 mg of HCQ and a constant dose of trametinib, observing a partial response with a general reduction of tumor lesion size, circulating tumor markers and cancer-associated pain.